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1
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Ullsten S, Østnes Hansen K, Petit GA, Hansen EH, Andersen JH. Promotion of beta cell proliferation through DYRK kinase inhibition using the marine natural product breitfussin C. Sci Rep 2025; 15:1247. [PMID: 39774736 PMCID: PMC11706957 DOI: 10.1038/s41598-025-85178-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 01/01/2025] [Indexed: 01/11/2025] Open
Abstract
Pro-inflammatory cytokines, like interleukin-1 beta and interferon gamma, are known to activate signalling pathways causing pancreatic beta cell death and dysfunction, contributing to the onset of diabetes. Targeting cytokine signalling pathways offers a potential strategy to slow or even halt disease progression, reducing reliance on exogenous insulin and improving glucose regulation. This study explores the protective and proliferative effects of breitfussin C (BfC), a natural compound isolated from the Arctic marine hydrozoan Thuiaria breitfussi, on pancreatic beta cells exposed to pro-inflammatory cytokines. Using the beta cell line RIN-M5F, we assessed the protective effects of BfC through a MTS assay for cell viability, caspase 3/7 activity for apoptosis, and EdU incorporation and cell cycle distribution for proliferation. Additionally, we investigated BfC's inhibitory effects on the DYRK family of kinases using kinase activity and binding assays, western blotting, and docking simulations. Our findings reveal that BfC treatment effectively increases beta cell proliferation and counteracts cytokine-induced decrease in proliferation. The proliferative effect is associated with inhibition of DYRK kinases and a subsequent decrease in the cell cycle inhibitor p27KIP. These results suggest that BfC mediates beta cell-protective effect by promoting proliferation through DYRK inhibition, highlighting its potential as a molecular starting point for the development of a therapeutic agent against diabetes.
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Affiliation(s)
- Sara Ullsten
- MARBIO, UiT - The Arctic University of Norway, Breivika, 9037, Tromsø, Norway
| | - Kine Østnes Hansen
- MARBIO, UiT - The Arctic University of Norway, Breivika, 9037, Tromsø, Norway
| | | | - Espen Holst Hansen
- MARBIO, UiT - The Arctic University of Norway, Breivika, 9037, Tromsø, Norway
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2
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Hammond T, Choi JB, Membreño MW, Demeter J, Ng R, Bhattacharya D, Nguyen TN, Hartmann GG, Bossard C, Skotheim JM, Jackson PK, Pasca A, Rubin SM, Sage J. THE FAM53C/DYRK1A axis regulates the G1/S transition of the cell cycle. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.10.627280. [PMID: 39713326 PMCID: PMC11661141 DOI: 10.1101/2024.12.10.627280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2024]
Abstract
A growing number of therapies are being developed to target the cell cycle machinery for the treatment of cancer and other human diseases. Consequently, a greater understanding of the factors regulating cell cycle progression becomes essential to help enhance the response to these new therapies. Here, using data from the Cancer Dependency Map, we identified the poorly-studied factor FAM53C as a new regulator of cell cycle progression. We found that FAM53C is critical for this cell cycle transition and that it acts upstream of the CyclinD-CDK4/6-RB axis in the regulation of the G1/S transition. By mass spectrometry, biochemical, and cellular assays, we identified and validated DYRK1A as a cell cycle kinase that is inhibited by and directly interacts with FAM53C. DYRK1A kinase inhibition rescues the G1 arrest induced by FAM53C knock-down. Consistent with the role for FAM53C identified in cells in culture, FAM53C knockout human cortical organoids display increased cell cycle arrest and growth defects. In addition, Fam53C knockout mice show defects in body growth and behavioral phenotypes. Because DYRK1A dysregulation contributes to developmental disorders such as Down syndrome as well as tumorigenesis, future strategies aiming at regulating FAM53C activity may benefit a broad range of patients.
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3
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Tu HJ, Chao MW, Lee CC, Peng CS, Wu YW, Lin TE, Chang YW, Yen SC, Hsu KC, Pan SL, HuangFu WC. Discovering a novel dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) inhibitor and its impact on tau phosphorylation and amyloid-β formation. J Enzyme Inhib Med Chem 2024; 39:2418470. [PMID: 39494990 PMCID: PMC11536634 DOI: 10.1080/14756366.2024.2418470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 09/25/2024] [Accepted: 10/12/2024] [Indexed: 11/05/2024] Open
Abstract
Dual-specificity tyrosine-regulated kinase 1 A (DYRK1A) is crucial in neurogenesis, synaptogenesis, and neuronal functions. Its dysregulation is linked to neurodegenerative disorders like Down syndrome and Alzheimer's disease. Although the development of DYRK1A inhibitors has significantly advanced in recent years, the selectivity of these drugs remains a critical challenge, potentially impeding further progress. In this study, we utilised structure-based virtual screening (SBVS) from NCI library to discover novel DYRK1A inhibitors. The top-ranked compounds were then validated through enzymatic assays to assess their efficacy towards DYRK1A. Among them, NSC361563 emerged as a potent and selective DYRK1A inhibitor. It was shown to decrease tau phosphorylation at multiple sites, thereby enhancing tubulin stability. Moreover, NSC361563 diminished the formation of amyloid β and offered neuroprotective benefits against amyloid β-induced toxicity. Our research highlights the critical role of selective DYRK1A inhibitors in treating neurodegenerative diseases and presents a promising starting point for the development of targeted therapies.
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Affiliation(s)
- Huang-Ju Tu
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Min-Wu Chao
- School of Medicine, College of Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan
- Institute of Biopharmaceutical Sciences, College of Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan
- The Doctoral Program of Clinical and Experimental Medicine, College of Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Cheng-Chung Lee
- The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Chao-Shiang Peng
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Yi-Wen Wu
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Tony Eight Lin
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Yu-Wei Chang
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung Medical Center, Keelung, Taiwan
| | - Shih-Chung Yen
- Warshel Institute for Computational Biology, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong, People’s Republic of China
| | - Kai-Cheng Hsu
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
| | - Shiow-Lin Pan
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
| | - Wei-Chun HuangFu
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
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4
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Gehlot P, Pathak R, Kumar S, Choudhary NK, Vyas VK. A review on synthetic inhibitors of dual-specific tyrosine phosphorylation-regulated kinase 1A (DYRK1A) for the treatment of Alzheimer's disease (AD). Bioorg Med Chem 2024; 113:117925. [PMID: 39357433 DOI: 10.1016/j.bmc.2024.117925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 09/09/2024] [Accepted: 09/10/2024] [Indexed: 10/04/2024]
Abstract
Alzheimer's disease (AD) is a complex disorder that is influenced by a number of variables, such as age, gender, environmental factors, disease, lifestyle, infections, and many more. The main characteristic of AD is the formation of amyloid plaque and neurofibrillary tangles (NFT), which are caused by various reasons such as inflammation, impairment of neurotransmitters, hyperphosphorylation of tau protein, generation of toxic amyloid beta (Aβ) 40/42, oxidative stress, etc. Protein kinases located in chromosome 21, namely dual-specific tyrosine phosphorylation-regulated kinase 1A (DYRK1A), play an essential role in the pathogenesis of AD. DYRK1A stimulates the Aβ peptide aggregation and phosphorylation of tau protein to generate the NFT formation that causes neurodegeneration. Thus, DYRK1A is associated with AD, and inhibition of DYRK1A has the potential to treat AD. In this review, we discussed the pathophysiology of AD, various factors responsible for AD, and the role of DYRK1A in AD. We have also discussed the latest therapeutic potential of DYRK1A inhibitors for neurogenerative disease, along with their structure-activity relationship (SAR) studies. This article provides valuable information for guiding the future discovery of novel and target-specific DYRK1A inhibitors over other kinases and their structural optimization to treat AD.
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Affiliation(s)
- Pinky Gehlot
- Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, Gujarat, India
| | - Rekha Pathak
- B R Nahata College of Pharmacy, Mandsaur University, Mandsaur 458001, Madhya Pradesh, India; Gyan Ganga Institute of Technology and Sciences, Jabalpur 482003, Madhya Pradesh, India
| | - Sunil Kumar
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi 221005, India
| | - Naveen Kumar Choudhary
- B R Nahata College of Pharmacy, Mandsaur University, Mandsaur 458001, Madhya Pradesh, India
| | - Vivek Kumar Vyas
- Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, Gujarat, India.
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5
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Wang P, Sarkar S, Zhang M, Xiao T, Kong F, Zhang Z, Balasubramanian D, Jayaram N, Datta S, He R, Wu P, Chao P, Zhang Y, Washburn M, Florens LA, Nagarkar-Jaiswal S, Jaiswal M, Mohan M. DYRK1A interacts with the tuberous sclerosis complex and promotes mTORC1 activity. eLife 2024; 12:RP88318. [PMID: 39436397 PMCID: PMC11495841 DOI: 10.7554/elife.88318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2024] Open
Abstract
DYRK1A, a ubiquitously expressed kinase, is linked to the dominant intellectual developmental disorder, microcephaly, and Down syndrome in humans. It regulates numerous cellular processes such as cell cycle, vesicle trafficking, and microtubule assembly. DYRK1A is a critical regulator of organ growth; however, how it regulates organ growth is not fully understood. Here, we show that the knockdown of DYRK1A in mammalian cells results in reduced cell size, which depends on mTORC1. Using proteomic approaches, we found that DYRK1A interacts with the tuberous sclerosis complex (TSC) proteins, namely TSC1 and TSC2, which negatively regulate mTORC1 activation. Furthermore, we show that DYRK1A phosphorylates TSC2 at T1462, a modification known to inhibit TSC activity and promote mTORC1 activity. We also found that the reduced cell growth upon knockdown of DYRK1A can be rescued by overexpression of RHEB, an activator of mTORC1. Our findings suggest that DYRK1A inhibits TSC complex activity through inhibitory phosphorylation on TSC2, thereby promoting mTORC1 activity. Furthermore, using the Drosophila neuromuscular junction as a model, we show that the mnb, the fly homologs of DYRK1A, is rescued by RHEB overexpression, suggesting a conserved role of DYRK1A in TORC1 regulation.
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Affiliation(s)
- Pinhua Wang
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and TechnologyKunmingChina
| | | | - Menghuan Zhang
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and TechnologyKunmingChina
| | - Tingting Xiao
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and TechnologyKunmingChina
| | - Fenhua Kong
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and TechnologyKunmingChina
| | - Zhe Zhang
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and TechnologyKunmingChina
| | | | - Nandan Jayaram
- CSIR–Centre for Cellular and Molecular BiologyHyderabadIndia
- Academy of Scientific and Innovative Research (AcSIR)GhaziabadIndia
| | | | - Ruyu He
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and TechnologyKunmingChina
| | - Ping Wu
- National Facility for Protein Science in Shanghai, Zhangjiang LabShanghaiChina
| | - Peng Chao
- National Facility for Protein Science in Shanghai, Zhangjiang LabShanghaiChina
| | - Ying Zhang
- Stowers Institute for Medical ResearchKansas CityUnited States
| | - Michael Washburn
- Stowers Institute for Medical ResearchKansas CityUnited States
- Department of Cancer Biology, The University of Kansas Medical CenterKansas CityUnited States
| | | | - Sonal Nagarkar-Jaiswal
- CSIR–Centre for Cellular and Molecular BiologyHyderabadIndia
- Academy of Scientific and Innovative Research (AcSIR)GhaziabadIndia
| | | | - Man Mohan
- State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and TechnologyKunmingChina
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiaotong University School of MedicineShanghaiChina
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6
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Vorwerk VA, Wilms G, Babendreyer A, Becker W. Differential regulation of expression of the protein kinases DYRK1A and DYRK1B in cancer cells. Sci Rep 2024; 14:23926. [PMID: 39397076 PMCID: PMC11471791 DOI: 10.1038/s41598-024-74190-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 09/24/2024] [Indexed: 10/15/2024] Open
Abstract
The protein kinases DYRK1A and DYRK1B are pivotal regulators of cell cycle progression by promoting cell cycle exit into quiescence. DYRK1B appears to play a more important role in cancer cell quiescence than DYRK1A, as evidenced by its overexpression or copy number variations in human tumour samples. Nonetheless, the stimuli driving DYRK1B upregulation and the potential divergence in expression patterns between DYRK1A and DYRK1B remain largely elusive. In the present study, we scrutinized the regulatory pathways modulating DYRK1B expression relative to DYRK1A in PANC-1 and A549 cancer cell lines across varying conditions. Serum deprivation, pharmacological mTOR inhibition and increased cell density resulted in the differential upregulation of DYRK1B compared to DYRK1A. We then aimed to assess the role of protein kinases MST1 and MST2, which are key transmitters of cell density dependent effects. Unexpectedly, exposure to the MST1/2 inhibitor XMU-MP-1 resulted in increased DYRK1B levels in A549 cells. Further investigation into the off-target effects of XMU-MP-1 unveiled the inhibition of Aurora kinases (AURKA and AURKB) as a potential causative factor. Consistently, AURK inhibitors VX-680 (tozasertib), MLN8237 (alisertib), AZD1152-HQPA (barasertib) resulted in the upregulation of DYRK1B expression in A549 cells. In summary, our findings indicate that the expression of DYRK1A and DYRK1B is differentially regulated in cancer cells and reveal that the kinase inhibitor XMU-MP-1 increases DYRK1B expression likely through off target inhibition of Aurora kinases.
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Affiliation(s)
- Vincent Andreas Vorwerk
- Institute of Pharmacology and Toxicology, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany
| | - Gerrit Wilms
- Institute of Pharmacology and Toxicology, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany
| | - Aaron Babendreyer
- Institute of Molecular Pharmacology, RWTH Aachen University, 52074, Aachen, Germany
| | - Walter Becker
- Institute of Pharmacology and Toxicology, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany.
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7
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Akere MT, Zajac KK, Bretz JD, Madhavaram AR, Horton AC, Schiefer IT. Real-Time Analysis of Neuronal Cell Cultures for CNS Drug Discovery. Brain Sci 2024; 14:770. [PMID: 39199464 PMCID: PMC11352746 DOI: 10.3390/brainsci14080770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 07/23/2024] [Accepted: 07/27/2024] [Indexed: 09/01/2024] Open
Abstract
The ability to screen for agents that can promote the development and/or maintenance of neuronal networks creates opportunities for the discovery of novel agents for the treatment of central nervous system (CNS) disorders. Over the past 10 years, advances in robotics, artificial intelligence, and machine learning have paved the way for the improved implementation of live-cell imaging systems for drug discovery. These instruments have revolutionized our ability to quickly and accurately acquire large standardized datasets when studying complex cellular phenomena in real-time. This is particularly useful in the field of neuroscience because real-time analysis can allow efficient monitoring of the development, maturation, and conservation of neuronal networks by measuring neurite length. Unfortunately, due to the relative infancy of this type of analysis, standard practices for data acquisition and processing are lacking, and there is no standardized format for reporting the vast quantities of data generated by live-cell imaging systems. This paper reviews the current state of live-cell imaging instruments, with a focus on the most commonly used equipment (IncuCyte systems). We provide an in-depth analysis of the experimental conditions reported in publications utilizing these systems, particularly with regard to studying neurite outgrowth. This analysis sheds light on trends and patterns that will enhance the use of live-cell imaging instruments in CNS drug discovery.
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Affiliation(s)
- Millicent T. Akere
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA; (M.T.A.); (K.K.Z.); (J.D.B.); (A.R.M.); (A.C.H.)
| | - Kelsee K. Zajac
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA; (M.T.A.); (K.K.Z.); (J.D.B.); (A.R.M.); (A.C.H.)
| | - James D. Bretz
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA; (M.T.A.); (K.K.Z.); (J.D.B.); (A.R.M.); (A.C.H.)
| | - Anvitha R. Madhavaram
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA; (M.T.A.); (K.K.Z.); (J.D.B.); (A.R.M.); (A.C.H.)
| | - Austin C. Horton
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA; (M.T.A.); (K.K.Z.); (J.D.B.); (A.R.M.); (A.C.H.)
| | - Isaac T. Schiefer
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA; (M.T.A.); (K.K.Z.); (J.D.B.); (A.R.M.); (A.C.H.)
- Center for Drug Design and Development, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA
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8
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Laham AJ, El-Awady R, Saber-Ayad M, Wang N, Yan G, Boudreault J, Ali S, Lebrun JJ. Targeting the DYRK1A kinase prevents cancer progression and metastasis and promotes cancer cells response to G1/S targeting chemotherapy drugs. NPJ Precis Oncol 2024; 8:128. [PMID: 38839871 PMCID: PMC11153725 DOI: 10.1038/s41698-024-00614-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 05/17/2024] [Indexed: 06/07/2024] Open
Abstract
Metastatic cancer remains incurable as patients eventually loose sensitivity to targeted therapies and chemotherapies, further leading to poor clinical outcome. Thus, there is a clear medical gap and urgent need to develop efficient and improved targeted therapies for cancer patients. In this study, we investigated the role of DYRK1A kinase in regulating cancer progression and evaluated the therapeutic potential of DYRK1A inhibition in invasive solid tumors, including colon and triple-negative breast cancers. We uncovered new roles played by the DYRK1A kinase. We found that blocking DYRK1A gene expression or pharmacological inhibition of its kinase activity via harmine efficiently blocked primary tumor formation and the metastatic tumor spread in preclinical models of breast and colon cancers. Further assessing the underlying molecular mechanisms, we found that DYRK1A inhibition resulted in increased expression of the G1/S cell cycle regulators while decreasing expression of the G2/M regulators. Combined, these effects release cancer cells from quiescence, leading to their accumulation in G1/S and further delaying/preventing their progression toward G2/M, ultimately leading to growth arrest and tumor growth inhibition. Furthermore, we show that accumulation of cancer cells in G1/S upon DYRK1A inhibition led to significant potentiation of G1/S targeting chemotherapy drug responses in vitro and in vivo. This study underscores the potential for developing novel DYRK1A-targeting therapies in colon and breast cancers and, at the same time, further defines DYRK1A pharmacological inhibition as a viable and powerful combinatorial treatment approach for improving G1/S targeting chemotherapy drugs treatments in solid tumors.
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Affiliation(s)
- Amina Jamal Laham
- Department of Medicine, Cancer Research Program, McGill University Health Center, Montreal, Quebec, H4A 3J1, Canada
- College of Medicine, University of Sharjah, Sharjah, 27272, United Arab Emirates
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Raafat El-Awady
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates.
- College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates.
| | - Maha Saber-Ayad
- College of Medicine, University of Sharjah, Sharjah, 27272, United Arab Emirates
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Ni Wang
- Department of Medicine, Cancer Research Program, McGill University Health Center, Montreal, Quebec, H4A 3J1, Canada
| | - Gang Yan
- Department of Medicine, Cancer Research Program, McGill University Health Center, Montreal, Quebec, H4A 3J1, Canada
| | - Julien Boudreault
- Department of Medicine, Cancer Research Program, McGill University Health Center, Montreal, Quebec, H4A 3J1, Canada
| | - Suhad Ali
- Department of Medicine, Cancer Research Program, McGill University Health Center, Montreal, Quebec, H4A 3J1, Canada
| | - Jean-Jacques Lebrun
- Department of Medicine, Cancer Research Program, McGill University Health Center, Montreal, Quebec, H4A 3J1, Canada.
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9
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Moreau M, Dard R, Madani A, Kandiah J, Kassis N, Ziga J, Castiglione H, Day S, Bourgeois T, Matrot B, Vialard F, Janel N. Prenatal treatment with preimplantation factor improves early postnatal neurogenesis and cognitive impairments in a mouse model of Down syndrome. Cell Mol Life Sci 2024; 81:215. [PMID: 38739166 DOI: 10.1007/s00018-024-05245-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 04/01/2024] [Accepted: 04/18/2024] [Indexed: 05/14/2024]
Abstract
Down syndrome (DS) is a genetic disease characterized by a supernumerary chromosome 21. Intellectual deficiency (ID) is one of the most prominent features of DS. Central nervous system defects lead to learning disabilities, motor and language delays, and memory impairments. At present, a prenatal treatment for the ID in DS is lacking. Subcutaneous administration of synthetic preimplantation factor (sPIF, a peptide with a range of biological functions) in a model of severe brain damage has shown neuroprotective and anti-inflammatory properties by directly targeting neurons and microglia. Here, we evaluated the effect of PIF administration during gestation and until weaning on Dp(16)1Yey mice (a mouse model of DS). Possible effects at the juvenile stage were assessed using behavioral tests and molecular and histological analyses of the brain. To test the influence of perinatal sPIF treatment at the adult stage, hippocampus-dependent memory was evaluated on postnatal day 90. Dp(16)1Yey pups showed significant behavioral impairment, with impaired neurogenesis, microglial cell activation and a low microglial cell count, and the deregulated expression of genes linked to neuroinflammation and cell cycle regulation. Treatment with sPIF restored early postnatal hippocampal neurogenesis, with beneficial effects on astrocytes, microglia, inflammation, and cell cycle markers. Moreover, treatment with sPIF restored the level of DYRK1A, a protein that is involved in cognitive impairments in DS. In line with the beneficial effects on neurogenesis, perinatal treatment with sPIF was associated with an improvement in working memory in adult Dp(16)1Yey mice. Perinatal treatment with sPIF might be an option for mitigating cognitive impairments in people with DS.
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Affiliation(s)
- Manon Moreau
- Université Paris Cité, BFA, UMR 8251, CNRS, Paris, F-75013, France
| | - Rodolphe Dard
- Université Paris Cité, BFA, UMR 8251, CNRS, Paris, F-75013, France
- Université Paris-Saclay, UVSQ, INRAE, ENVA, BREED, Jouy-en-Josas, 78350, France
- Département de Génétique, CHI de Poissy St Germain en Laye, Poissy, 78300, France
| | - Amélia Madani
- NeuroDiderot, INSERM, Université Paris Cité, Paris, F-75019, France
| | - Janany Kandiah
- Université Paris Cité, BFA, UMR 8251, CNRS, Paris, F-75013, France
| | - Nadim Kassis
- Université Paris Cité, BFA, UMR 8251, CNRS, Paris, F-75013, France
| | - Jessica Ziga
- Université Paris Cité, BFA, UMR 8251, CNRS, Paris, F-75013, France
| | | | - Solenn Day
- Université Paris Cité, BFA, UMR 8251, CNRS, Paris, F-75013, France
| | - Thomas Bourgeois
- NeuroDiderot, INSERM, Université Paris Cité, Paris, F-75019, France
| | - Boris Matrot
- NeuroDiderot, INSERM, Université Paris Cité, Paris, F-75019, France
| | - François Vialard
- Université Paris-Saclay, UVSQ, INRAE, ENVA, BREED, Jouy-en-Josas, 78350, France
- Département de Génétique, CHI de Poissy St Germain en Laye, Poissy, 78300, France
| | - Nathalie Janel
- Université Paris Cité, BFA, UMR 8251, CNRS, Paris, F-75013, France.
- Laboratoire BFA, Université Paris Cité, 3 rue Marie-Andrée Lagroua Weill Hallé, Case, Paris cedex 13, 7104, F-75205, France.
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10
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Kokkorakis N, Douka K, Nalmpanti A, Politis PK, Zagoraiou L, Matsas R, Gaitanou M. Mirk/Dyrk1B controls ventral spinal cord development via Shh pathway. Cell Mol Life Sci 2024; 81:70. [PMID: 38294527 PMCID: PMC10830675 DOI: 10.1007/s00018-023-05097-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 12/14/2023] [Accepted: 12/17/2023] [Indexed: 02/01/2024]
Abstract
Cross-talk between Mirk/Dyrk1B kinase and Sonic hedgehog (Shh)/Gli pathway affects physiology and pathology. Here, we reveal a novel role for Dyrk1B in regulating ventral progenitor and neuron subtypes in the embryonic chick spinal cord (SC) via the Shh pathway. Using in ovo gain-and-loss-of-function approaches at E2, we report that Dyrk1B affects the proliferation and differentiation of neuronal progenitors at E4 and impacts on apoptosis specifically in the motor neuron (MN) domain. Especially, Dyrk1B overexpression decreases the numbers of ventral progenitors, MNs, and V2a interneurons, while the pharmacological inhibition of endogenous Dyrk1B kinase activity by AZ191 administration increases the numbers of ventral progenitors and MNs. Mechanistically, Dyrk1B overexpression suppresses Shh, Gli2 and Gli3 mRNA levels, while conversely, Shh, Gli2 and Gli3 transcription is increased in the presence of Dyrk1B inhibitor AZ191 or Smoothened agonist SAG. Most importantly, in phenotype rescue experiments, SAG restores the Dyrk1B-mediated dysregulation of ventral progenitors. Further at E6, Dyrk1B affects selectively the medial lateral motor neuron column (LMCm), consistent with the expression of Shh in this region. Collectively, these observations reveal a novel regulatory function of Dyrk1B kinase in suppressing the Shh/Gli pathway and thus affecting ventral subtypes in the developing spinal cord. These data render Dyrk1B a possible therapeutic target for motor neuron diseases.
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Affiliation(s)
- N Kokkorakis
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, Athens, Greece
- Division of Animal and Human Physiology, Department of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - K Douka
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, Athens, Greece
| | - A Nalmpanti
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, Athens, Greece
- Athens International Master's Programme in Neurosciences, Department of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - P K Politis
- Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
- School of Medicine, European University Cyprus, Nicosia, Cyprus
| | - L Zagoraiou
- School of Medicine, European University Cyprus, Nicosia, Cyprus
| | - R Matsas
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, Athens, Greece
| | - M Gaitanou
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, Athens, Greece.
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11
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Gao M, Zhang T, Chen T, Chen Z, Zhu Z, Wen Y, Qin S, Bao Y, Zhao T, Li H, Liu L, Hao M, Wang J, Wang F, Wang H, Zhou B, Zhang H, Xia G, Wang C. Polycomb repressive complex 1 modulates granulosa cell proliferation in early folliculogenesis to support female reproduction. Theranostics 2024; 14:1371-1389. [PMID: 38389850 PMCID: PMC10879878 DOI: 10.7150/thno.89878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 01/10/2024] [Indexed: 02/24/2024] Open
Abstract
Rationale: Premature ovarian insufficiency (POI) is an accelerated reduction in ovarian function inducing infertility. Folliculogenesis defects have been reported to trigger POI as a consequence of ovulation failure. However, the underlying mechanisms remain unclear due to the genetic complexity and heterogeneity of POI. Methods: We used whole genome sequencing (WGS), conditional knockout mouse models combined with laser capture microdissection (LCM), and RNA/ChIP sequencing to analyze the crucial roles of polycomb repressive complex 1 (PRC1) in clinical POI and mammalian folliculogenesis. Results: A deletion mutation of MEL18, the key component of PRC1, was identified in a 17-year-old patient. However, deleting Mel18 in granulosa cells (GCs) did not induce infertility until its homolog, Bmi1, was deleted simultaneously. Double deficiency of BMI1/MEL18 eliminated PRC1 catalytic activity, upregulating cyclin-dependent kinase inhibitors (CDKIs) and thus blocking GC proliferation during primary-to-secondary follicle transition. This defect led to damaged intercellular crosstalk, eventually resulting in gonadotropin response failure and infertility. Conclusions: Our findings highlighted the pivotal role of PRC1 as an epigenetic regulator of gene transcription networks in GC proliferation during early folliculogenesis. In the future, a better understanding of molecular details of PRC1 structural and functional abnormalities may contribute to POI diagnosis and therapeutic options.
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Affiliation(s)
- Meng Gao
- State Key Laboratory of Farm Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing 100193, China
| | - Tuo Zhang
- Guizhou Provincial Key Laboratory of Pathogenesis & Drug Research on Common Chronic Diseases, Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Department of Physiology, College of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou Province, 550025, China
| | - Tengxiang Chen
- Guizhou Provincial Key Laboratory of Pathogenesis & Drug Research on Common Chronic Diseases, Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Department of Physiology, College of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou Province, 550025, China
| | - Ziqi Chen
- State Key Laboratory of Farm Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing 100193, China
| | - Zijian Zhu
- State Key Laboratory of Farm Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing 100193, China
| | - Yang Wen
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Shaogang Qin
- State Key Laboratory of Farm Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing 100193, China
| | - Yibing Bao
- State Key Laboratory of Farm Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing 100193, China
| | - Ting Zhao
- State Key Laboratory of Farm Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing 100193, China
| | - Hengxing Li
- State Key Laboratory of Farm Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing 100193, China
| | - Longping Liu
- School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Ming Hao
- School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Jianbin Wang
- School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Fengchao Wang
- Transgenic Animal Center, National Institute of Biological Sciences, Beijing, 102206, China
| | - Haibin Wang
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian Province, 361005, China
| | - Bo Zhou
- State Key Laboratory of Farm Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing 100193, China
| | - Hua Zhang
- State Key Laboratory of Farm Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing 100193, China
| | - Guoliang Xia
- State Key Laboratory of Farm Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing 100193, China
- Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in Western China, College of Life Science, Ningxia University, Yinchuan, 750021, China
| | - Chao Wang
- State Key Laboratory of Farm Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing 100193, China
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12
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Lana-Elola E, Aoidi R, Llorian M, Gibbins D, Buechsenschuetz C, Bussi C, Flynn H, Gilmore T, Watson-Scales S, Haugsten Hansen M, Hayward D, Song OR, Brault V, Herault Y, Deau E, Meijer L, Snijders AP, Gutierrez MG, Fisher EMC, Tybulewicz VLJ. Increased dosage of DYRK1A leads to congenital heart defects in a mouse model of Down syndrome. Sci Transl Med 2024; 16:eadd6883. [PMID: 38266108 PMCID: PMC7615651 DOI: 10.1126/scitranslmed.add6883] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 12/22/2023] [Indexed: 01/26/2024]
Abstract
Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21). DS is a gene dosage disorder that results in multiple phenotypes including congenital heart defects. This clinically important cardiac pathology is the result of a third copy of one or more of the approximately 230 genes on Hsa21, but the identity of the causative dosage-sensitive genes and hence mechanisms underlying this cardiac pathology remain unclear. Here, we show that hearts from human fetuses with DS and embryonic hearts from the Dp1Tyb mouse model of DS show reduced expression of mitochondrial respiration genes and cell proliferation genes. Using systematic genetic mapping, we determined that three copies of the dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1a) gene, encoding a serine/threonine protein kinase, are associated with congenital heart disease pathology. In embryos from Dp1Tyb mice, reducing Dyrk1a gene copy number from three to two reversed defects in cellular proliferation and mitochondrial respiration in cardiomyocytes and rescued heart septation defects. Increased dosage of DYRK1A protein resulted in impairment of mitochondrial function and congenital heart disease pathology in mice with DS, suggesting that DYRK1A may be a useful therapeutic target for treating this common human condition.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | - Véronique Brault
- Université de Strasbourg, CNRS UMR7104, INSERM U1258, Institut de Génétique et de Biologie Moléculaire et Cellulaire, IGBMC, BP 10142, 1 rue Laurent Fries, 67404 Illkirch CEDEX, France
| | - Yann Herault
- Université de Strasbourg, CNRS UMR7104, INSERM U1258, Institut de Génétique et de Biologie Moléculaire et Cellulaire, IGBMC, BP 10142, 1 rue Laurent Fries, 67404 Illkirch CEDEX, France
| | - Emmanuel Deau
- Perha Pharmaceuticals, Presqu'île de Perharidy, 29680 Roscoff, France
| | - Laurent Meijer
- Perha Pharmaceuticals, Presqu'île de Perharidy, 29680 Roscoff, France
| | | | | | - Elizabeth M C Fisher
- Department of Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK
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13
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Fu Z, Xiang Y, Fu Y, Su Z, Tan Y, Yang M, Yan Y, Baghaei Daemi H, Shi Y, Xie S, Sun L, Peng G. DYRK1A is a multifunctional host factor that regulates coronavirus replication in a kinase-independent manner. J Virol 2024; 98:e0123923. [PMID: 38099687 PMCID: PMC10805018 DOI: 10.1128/jvi.01239-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 11/27/2023] [Indexed: 01/24/2024] Open
Abstract
Coronaviruses (CoVs) pose a major threat to human and animal health worldwide, which complete viral replication by hijacking host factors. Identifying host factors essential for the viral life cycle can deepen our understanding of the mechanisms of virus-host interactions. Based on our previous genome-wide CRISPR screen of α-CoV transmissible gastroenteritis virus (TGEV), we identified the host factor dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), but not DYRK1B, as a critical factor in TGEV replication. Rescue assays and kinase inhibitor experiments revealed that the effect of DYRK1A on viral replication is independent of its kinase activity. Nuclear localization signal modification experiments showed that nuclear DYRK1A facilitated virus replication. Furthermore, DYRK1A knockout significantly downregulated the expression of the TGEV receptor aminopeptidase N (ANPEP) and inhibited viral entry. Notably, we also demonstrated that DYRK1A is essential for the early stage of TGEV replication. Transmission electron microscopy results indicated that DYRK1A contributes to the formation of double-membrane vesicles in a kinase-independent manner. Finally, we validated that DYRK1A is also a proviral factor for mouse hepatitis virus, porcine deltacoronavirus, and porcine sapelovirus. In conclusion, our work demonstrated that DYRK1A is an essential host factor for the replication of multiple viruses, providing new insights into the mechanism of virus-host interactions and facilitating the development of new broad-spectrum antiviral drugs.IMPORTANCECoronaviruses, like other positive-sense RNA viruses, can remodel the host membrane to form double-membrane vesicles (DMVs) as their replication organelles. Currently, host factors involved in DMV formation are not well defined. In this study, we used transmissible gastroenteritis virus (TGEV) as a virus model to investigate the regulatory mechanism of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) on coronavirus. Results showed that DYRK1A significantly inhibited TGEV replication in a kinase-independent manner. DYRK1A knockout (KO) can regulate the expression of receptor aminopeptidase N (ANPEP) and endocytic-related genes to inhibit virus entry. More importantly, our results revealed that DYRK1A KO notably inhibited the formation of DMV to regulate the virus replication. Further data proved that DYRK1A is also essential in the replication of mouse hepatitis virus, porcine deltacoronavirus, and porcine sapelovirus. Taken together, our findings demonstrated that DYRK1A is a conserved factor for positive-sense RNA viruses and provided new insights into its transcriptional regulation activity, revealing its potential as a candidate target for therapeutic design.
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Affiliation(s)
- Zhen Fu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
| | - Yixin Xiang
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
| | - Yanan Fu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
| | - Zhelin Su
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
| | - Yubei Tan
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
| | - Mengfang Yang
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
| | - Yuanyuan Yan
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
| | - Hakimeh Baghaei Daemi
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
| | - Yuejun Shi
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
| | - Shengsong Xie
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education & Key Lab of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan, China
| | - Limeng Sun
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
| | - Guiqing Peng
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Prevention & Control for African Swine Fever and Other Major Pig Diseases, Ministry of Agriculture and Rural Affairs, Wuhan, China
- Hubei Hongshan Laboratory, Frontiers Science Center for Animal Breeding and Sustainable Production, Wuhan, China
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14
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Hawley LE, Stringer M, Deal AJ, Folz A, Goodlett CR, Roper RJ. Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model. Neurobiol Dis 2024; 190:106359. [PMID: 37992782 PMCID: PMC10843801 DOI: 10.1016/j.nbd.2023.106359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 11/02/2023] [Accepted: 11/18/2023] [Indexed: 11/24/2023] Open
Abstract
Aberrant neurodevelopment in Down syndrome (DS)-caused by triplication of human chromosome 21-is commonly attributed to gene dosage imbalance, linking overexpression of trisomic genes with disrupted developmental processes, with DYRK1A particularly implicated. We hypothesized that regional brain DYRK1A protein overexpression in trisomic mice varies over development in sex-specific patterns that may be distinct from Dyrk1a transcription, and reduction of Dyrk1a copy number from 3 to 2 in otherwise trisomic mice reduces DYRK1A, independent of other trisomic genes. DYRK1A overexpression varied with age, sex, and brain region, with peak overexpression on postnatal day (P) 6 in both sexes. Sex-dependent differences were also evident from P15-P24. Reducing Dyrk1a copy number confirmed that these differences depended on Dyrk1a gene dosage and not other trisomic genes. Trisomic Dyrk1a mRNA and protein expression were not highly correlated. Sex-specific patterns of DYRK1A overexpression during trisomic neurodevelopment may provide mechanistic targets for therapeutic intervention in DS.
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Affiliation(s)
- Laura E Hawley
- Department of Biology, Indiana University - Purdue University Indianapolis, 723 W. Michigan Street, SL306, Indianapolis, IN, 46202, USA
| | - Megan Stringer
- Department of Psychology, Indiana University - Purdue University Indianapolis, 402 N. Blackford Street, LD124, Indianapolis, IN, 46202, USA
| | - Abigail J Deal
- Department of Biology, Indiana University - Purdue University Indianapolis, 723 W. Michigan Street, SL306, Indianapolis, IN, 46202, USA
| | - Andrew Folz
- Department of Biology, Indiana University - Purdue University Indianapolis, 723 W. Michigan Street, SL306, Indianapolis, IN, 46202, USA
| | - Charles R Goodlett
- Department of Psychology, Indiana University - Purdue University Indianapolis, 402 N. Blackford Street, LD124, Indianapolis, IN, 46202, USA
| | - Randall J Roper
- Department of Biology, Indiana University - Purdue University Indianapolis, 723 W. Michigan Street, SL306, Indianapolis, IN, 46202, USA.
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15
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Bhat Y, Thrishna MR, Banerjee S. Molecular targets and therapeutic strategies for triple-negative breast cancer. Mol Biol Rep 2023; 50:10535-10577. [PMID: 37924450 DOI: 10.1007/s11033-023-08868-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 09/29/2023] [Indexed: 11/06/2023]
Abstract
Triple-negative breast cancer (TNBC) is known for its heterogeneous complexity and is often difficult to treat. TNBC lacks the expression of major hormonal receptors like estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 and is further subdivided into androgen receptor (AR) positive and AR negative. In contrast, AR negative is also known as quadruple-negative breast cancer (QNBC). Compared to AR-positive TNBC, QNBC has a great scarcity of prognostic biomarkers and therapeutic targets. QNBC shows excessive cellular growth and proliferation of tumor cells due to increased expression of growth factors like EGF and various surface proteins. This study briefly reviews the limited data available as protein biomarkers that can be used as molecular targets in treating TNBC as well as QNBC. Targeted therapy and immune checkpoint inhibitors have recently changed cancer treatment. Many studies in medicinal chemistry continue to focus on the synthesis of novel compounds to discover new antiproliferative medicines capable of treating TNBC despite the abundance of treatments currently on the market. Drug repurposing is one of the therapeutic methods for TNBC that has been examined. Moreover, some additional micronutrients, nutraceuticals, and functional foods may be able to lower cancer risk or slow the spread of malignant diseases that have already been diagnosed with cancer. Finally, nanomedicines, or applications of nanotechnology in medicine, introduce nanoparticles with variable chemistry and architecture for the treatment of cancer. This review emphasizes the most recent research on nutraceuticals, medication repositioning, and novel therapeutic strategies for the treatment of TNBC.
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Affiliation(s)
- Yashasvi Bhat
- School of Bio Science and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - M R Thrishna
- School of Bio Science and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Satarupa Banerjee
- School of Bio Science and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India.
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16
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Sit YT, Takasaki K, An HH, Xiao Y, Hurtz C, Gearhart PA, Zhang Z, Gadue P, French DL, Chou ST. Synergistic roles of DYRK1A and GATA1 in trisomy 21 megakaryopoiesis. JCI Insight 2023; 8:e172851. [PMID: 37906251 PMCID: PMC10895998 DOI: 10.1172/jci.insight.172851] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 10/25/2023] [Indexed: 11/02/2023] Open
Abstract
Patients with Down syndrome (DS), or trisomy 21 (T21), are at increased risk of transient abnormal myelopoiesis (TAM) and acute megakaryoblastic leukemia (ML-DS). Both TAM and ML-DS require prenatal somatic mutations in GATA1, resulting in the truncated isoform GATA1s. The mechanism by which individual chromosome 21 (HSA21) genes synergize with GATA1s for leukemic transformation is challenging to study, in part due to limited human cell models with wild-type GATA1 (wtGATA1) or GATA1s. HSA21-encoded DYRK1A is overexpressed in ML-DS and may be a therapeutic target. To determine how DYRK1A influences hematopoiesis in concert with GATA1s, we used gene editing to disrupt all 3 alleles of DYRK1A in isogenic T21 induced pluripotent stem cells (iPSCs) with and without the GATA1s mutation. Unexpectedly, hematopoietic differentiation revealed that DYRK1A loss combined with GATA1s leads to increased megakaryocyte proliferation and decreased maturation. This proliferative phenotype was associated with upregulation of D-type cyclins and hyperphosphorylation of Rb to allow E2F release and derepression of its downstream targets. Notably, DYRK1A loss had no effect in T21 iPSCs or megakaryocytes with wtGATA1. These surprising results suggest that DYRK1A and GATA1 may synergistically restrain megakaryocyte proliferation in T21 and that DYRK1A inhibition may not be a therapeutic option for GATA1s-associated leukemias.
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Affiliation(s)
- Ying Ting Sit
- Division of Hematology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Kaoru Takasaki
- Division of Hematology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Hyun Hyung An
- Division of Hematology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Yan Xiao
- Division of Hematology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Christian Hurtz
- Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Peter A. Gearhart
- Deparment of Obstetrics and Gynecology, Pennsylvania Hospital, University of Pennsylvania Health System, Philadelphia, Pennsylvania, USA
| | - Zhe Zhang
- Department of Biomedical Informatics and
| | - Paul Gadue
- Center for Cellular and Molecular Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Deborah L. French
- Center for Cellular and Molecular Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Stella T. Chou
- Division of Hematology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
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17
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Ananthapadmanabhan V, Shows KH, Dickinson AJ, Litovchick L. Insights from the protein interaction Universe of the multifunctional "Goldilocks" kinase DYRK1A. Front Cell Dev Biol 2023; 11:1277537. [PMID: 37900285 PMCID: PMC10600473 DOI: 10.3389/fcell.2023.1277537] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 10/02/2023] [Indexed: 10/31/2023] Open
Abstract
Human Dual specificity tyrosine (Y)-Regulated Kinase 1A (DYRK1A) is encoded by a dosage-dependent gene located in the Down syndrome critical region of human chromosome 21. The known substrates of DYRK1A include proteins involved in transcription, cell cycle control, DNA repair and other processes. However, the function and regulation of this kinase is not fully understood, and the current knowledge does not fully explain the dosage-dependent function of this kinase. Several recent proteomic studies identified DYRK1A interacting proteins in several human cell lines. Interestingly, several of known protein substrates of DYRK1A were undetectable in these studies, likely due to a transient nature of the kinase-substrate interaction. It is possible that the stronger-binding DYRK1A interacting proteins, many of which are poorly characterized, are involved in regulatory functions by recruiting DYRK1A to the specific subcellular compartments or distinct signaling pathways. Better understanding of these DYRK1A-interacting proteins could help to decode the cellular processes regulated by this important protein kinase during embryonic development and in the adult organism. Here, we review the current knowledge of the biochemical and functional characterization of the DYRK1A protein-protein interaction network and discuss its involvement in human disease.
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Affiliation(s)
- Varsha Ananthapadmanabhan
- Department of Internal Medicine, Division of Hematology, Oncology and Palliative Care, Virginia Commonwealth University, Richmond, VA, United States
| | - Kathryn H. Shows
- Department of Biology, Virginia State University, Petersburg, VA, United States
| | - Amanda J. Dickinson
- Department of Biology, Virginia Commonwealth University, Richmond, VA, United States
| | - Larisa Litovchick
- Department of Internal Medicine, Division of Hematology, Oncology and Palliative Care, Virginia Commonwealth University, Richmond, VA, United States
- Massey Cancer Center, Richmond, VA, United States
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18
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Hogg EKJ, Findlay GM. Functions of SRPK, CLK and DYRK kinases in stem cells, development, and human developmental disorders. FEBS Lett 2023; 597:2375-2415. [PMID: 37607329 PMCID: PMC10952393 DOI: 10.1002/1873-3468.14723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 07/08/2023] [Accepted: 07/18/2023] [Indexed: 08/24/2023]
Abstract
Human developmental disorders encompass a wide range of debilitating physical conditions and intellectual disabilities. Perturbation of protein kinase signalling underlies the development of some of these disorders. For example, disrupted SRPK signalling is associated with intellectual disabilities, and the gene dosage of DYRKs can dictate the pathology of disorders including Down's syndrome. Here, we review the emerging roles of the CMGC kinase families SRPK, CLK, DYRK, and sub-family HIPK during embryonic development and in developmental disorders. In particular, SRPK, CLK, and DYRK kinase families have key roles in developmental signalling and stem cell regulation, and can co-ordinate neuronal development and function. Genetic studies in model organisms reveal critical phenotypes including embryonic lethality, sterility, musculoskeletal errors, and most notably, altered neurological behaviours arising from defects of the neuroectoderm and altered neuronal signalling. Further unpicking the mechanisms of specific kinases using human stem cell models of neuronal differentiation and function will improve our understanding of human developmental disorders and may provide avenues for therapeutic strategies.
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Affiliation(s)
- Elizabeth K. J. Hogg
- The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life SciencesUniversity of DundeeUK
| | - Greg M. Findlay
- The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life SciencesUniversity of DundeeUK
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19
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Fleifel D, Cook JG. G1 Dynamics at the Crossroads of Pluripotency and Cancer. Cancers (Basel) 2023; 15:4559. [PMID: 37760529 PMCID: PMC10526231 DOI: 10.3390/cancers15184559] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 08/29/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
G1 cell cycle phase dynamics are regulated by intricate networks involving cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors, which control G1 progression and ensure proper cell cycle transitions. Moreover, adequate origin licensing in G1 phase, the first committed step of DNA replication in the subsequent S phase, is essential to maintain genome integrity. In this review, we highlight the intriguing parallels and disparities in G1 dynamics between stem cells and cancer cells, focusing on their regulatory mechanisms and functional outcomes. Notably, SOX2, OCT4, KLF4, and the pluripotency reprogramming facilitator c-MYC, known for their role in establishing and maintaining stem cell pluripotency, are also aberrantly expressed in certain cancer cells. In this review, we discuss recent advances in understanding the regulatory role of these pluripotency factors in G1 dynamics in the context of stem cells and cancer cells, which may offer new insights into the interconnections between pluripotency and tumorigenesis.
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Affiliation(s)
| | - Jeanette Gowen Cook
- Department of Biochemistry & Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;
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20
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Tan S, Zhao J, Wang P. DYRK1A-mediated PLK2 phosphorylation regulates the proliferation and invasion of glioblastoma cells. Int J Oncol 2023; 63:94. [PMID: 37387444 PMCID: PMC10552692 DOI: 10.3892/ijo.2023.5542] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 06/13/2023] [Indexed: 07/01/2023] Open
Abstract
Polo-like kinases (PLKs) are a family of serine-threonine kinases that exert regulatory effects on diverse cellular processes. Dysregulation of PLKs has been implicated in multiple cancers, including glioblastoma (GBM). Notably, PLK2 expression in GBM tumor tissue is lower than that in normal brains. Notably, high PLK2 expression is significantly correlated with poor prognosis. Thus, it can be inferred that PLK2 expression alone may not be sufficient for accurate prognosis evaluation, and there are unknown mechanisms underlying PLK2 regulation. In the present study, it was demonstrated that dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) interacts with and phosphorylates PLK2 at Ser358. DYRK1A-mediated phosphorylation of PLK2 increases its protein stability. Moreover, PLK2 kinase activity was markedly induced by DYRK1A, which was exemplified by the upregulation of alpha-synuclein S129 phosphorylation. Furthermore, it was found that phosphorylation of PLK2 by DYRK1A contributes to the proliferation, migration and invasion of GBM cells. DYRK1A further enhances the inhibition of the malignancy of GBM cells already induced by PLK2. The findings of the present study indicate that PLK2 may play a crucial role in GBM pathogenesis partially in a DYRK1A-dependent manner, suggesting that PLK2 Ser358 may serve as a therapeutic target for GBM.
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Affiliation(s)
- Shichuan Tan
- Department of Otorhinolaryngology, Qilu Hospital of Shandong University, National Health Commission (NHC) Key Laboratory of Otorhinolaryngology, Shandong University
- Department of Emergency Neurosurgical Intensive Care Unit, Qilu Hospital of Shandong University
- Department of Neurosurgery, Qilu Hospital and Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Juan Zhao
- Department of Otorhinolaryngology, Qilu Hospital of Shandong University, National Health Commission (NHC) Key Laboratory of Otorhinolaryngology, Shandong University
| | - Pin Wang
- Department of Otorhinolaryngology, Qilu Hospital of Shandong University, National Health Commission (NHC) Key Laboratory of Otorhinolaryngology, Shandong University
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21
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Strine MS, Cai WL, Wei J, Alfajaro MM, Filler RB, Biering SB, Sarnik S, Chow RD, Patil A, Cervantes KS, Collings CK, DeWeirdt PC, Hanna RE, Schofield K, Hulme C, Konermann S, Doench JG, Hsu PD, Kadoch C, Yan Q, Wilen CB. DYRK1A promotes viral entry of highly pathogenic human coronaviruses in a kinase-independent manner. PLoS Biol 2023; 21:e3002097. [PMID: 37310920 PMCID: PMC10263356 DOI: 10.1371/journal.pbio.3002097] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 03/29/2023] [Indexed: 06/15/2023] Open
Abstract
Identifying host genes essential for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has the potential to reveal novel drug targets and further our understanding of Coronavirus Disease 2019 (COVID-19). We previously performed a genome-wide CRISPR/Cas9 screen to identify proviral host factors for highly pathogenic human coronaviruses. Few host factors were required by diverse coronaviruses across multiple cell types, but DYRK1A was one such exception. Although its role in coronavirus infection was previously undescribed, DYRK1A encodes Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1A and is known to regulate cell proliferation and neuronal development. Here, we demonstrate that DYRK1A regulates ACE2 and DPP4 transcription independent of its catalytic kinase function to support SARS-CoV, SARS-CoV-2, and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) entry. We show that DYRK1A promotes DNA accessibility at the ACE2 promoter and a putative distal enhancer, facilitating transcription and gene expression. Finally, we validate that the proviral activity of DYRK1A is conserved across species using cells of nonhuman primate and human origin. In summary, we report that DYRK1A is a novel regulator of ACE2 and DPP4 expression that may dictate susceptibility to multiple highly pathogenic human coronaviruses.
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Affiliation(s)
- Madison S. Strine
- Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Wesley L. Cai
- Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America
| | - Jin Wei
- Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei Province, China
| | - Mia Madel Alfajaro
- Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Renata B. Filler
- Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Scott B. Biering
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, California, United States of America
| | - Sylvia Sarnik
- University of Colorado Boulder, Boulder, Colorado, United States of America
| | - Ryan D. Chow
- Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Ajinkya Patil
- Department of Pediatric Oncology, Dana–Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, United States of America
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
- Program in Virology, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Kasey S. Cervantes
- Department of Pediatric Oncology, Dana–Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, United States of America
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
| | - Clayton K. Collings
- Department of Pediatric Oncology, Dana–Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, United States of America
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
| | - Peter C. DeWeirdt
- Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
| | - Ruth E. Hanna
- Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
| | - Kevin Schofield
- Department of Chemistry and Biochemistry, College of Science, The University of Arizona, Tucson, Arizona, United States of America
| | - Christopher Hulme
- Department of Chemistry and Biochemistry, College of Science, The University of Arizona, Tucson, Arizona, United States of America
- Division of Drug Discovery and Development, Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona, United States of America
| | - Silvana Konermann
- Department of Biochemistry, Stanford University School of Medicine, Stanford, California, United States of America
- Arc Institute, Palo Alto, California, United States of America
| | - John G. Doench
- Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
| | - Patrick D. Hsu
- Arc Institute, Palo Alto, California, United States of America
- Department of Bioengineering, University of California, Berkeley, Berkeley, California, United States of America
- Innovative Genomics Institute, University of California, Berkeley, Berkeley, California, United States of America
- Center for Computational Biology, University of California, Berkeley, California, United States of America
| | - Cigall Kadoch
- Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, United States of America
- Department of Pediatric Oncology, Dana–Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, United States of America
- Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America
| | - Qin Yan
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut, United States of America
- Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Craig B. Wilen
- Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America
- Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, United States of America
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22
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Peng L, Baradar AA, Aguado J, Wolvetang E. Cellular senescence and premature aging in Down Syndrome. Mech Ageing Dev 2023; 212:111824. [PMID: 37236373 DOI: 10.1016/j.mad.2023.111824] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 05/15/2023] [Accepted: 05/23/2023] [Indexed: 05/28/2023]
Abstract
Down syndrome (DS) is a genetic disorder caused by an extra copy of chromosome 21, resulting in cognitive impairment, physical abnormalities, and an increased risk of age-related co-morbidities. Individuals with DS exhibit accelerated aging, which has been attributed to several cellular mechanisms, including cellular senescence, a state of irreversible cell cycle arrest that is associated with aging and age-related diseases. Emerging evidence suggests that cellular senescence may play a key role in the pathogenesis of DS and the development of age-related disorders in this population. Importantly, cellular senescence may be a potential therapeutic target in alleviating age-related DS pathology. Here, we discuss the importance of focusing on cellular senescence to understand accelerated aging in DS. We review the current state of knowledge regarding cellular senescence and other hallmarks of aging in DS, including its putative contribution to cognitive impairment, multi-organ dysfunction, and premature aging phenotypes.
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Affiliation(s)
- Lianli Peng
- Australian Institute for Biotechnology and Nanotechnology, University of Queensland, St Lucia, QLD 4072, Australia
| | - Alireza A Baradar
- Australian Institute for Biotechnology and Nanotechnology, University of Queensland, St Lucia, QLD 4072, Australia
| | - Julio Aguado
- Australian Institute for Biotechnology and Nanotechnology, University of Queensland, St Lucia, QLD 4072, Australia.
| | - Ernst Wolvetang
- Australian Institute for Biotechnology and Nanotechnology, University of Queensland, St Lucia, QLD 4072, Australia.
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23
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Pucelik B, Barzowska A, Czarna A. DYRK1A inhibitors leucettines and TGF-β inhibitor additively stimulate insulin production in beta cells, organoids, and isolated mouse islets. PLoS One 2023; 18:e0285208. [PMID: 37195917 PMCID: PMC10191338 DOI: 10.1371/journal.pone.0285208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Accepted: 04/18/2023] [Indexed: 05/19/2023] Open
Abstract
The decreased β-cell mass and impaired β-cell functionality are the primary causes of diabetes mellitus (DM). Nevertheless, the underlying molecular mechanisms by which β-cell growth and function are controlled are not fully understood. In this work, we show that leucettines, known to be DYRK1A kinase inhibitors, can improve glucose-stimulated insulin secretion (GSIS) in rodent β-cells and isolated islets, as well as in hiPSC-derived β-cells islets. We confirm that DYRK1A is expressed in murine insulinoma cells MIN6. In addition, we found that treatment with selected leucettines stimulates proliferation of β-cells and promotes MIN6 cell cycle progression to the G2/M phase. This effect is also confirmed by increased levels of cyclin D1, which is highly responsive to proliferative signals. Among other leucettines, leucettine L43 had a negligible impact on β-cell proliferation, but markedly impair GSIS. However, leucettine L41, in combination with LY364947, a, a potent and selective TGF-β type-I receptor, significantly promotes GSIS in various cellular diabetic models, including MIN6 and INS1E cells in 2D and 3D culture, iPSC-derived β-cell islets derived from iPSC, and isolated mouse islets, by increased insulin secretion and decreased glucagon level. Our findings confirm an important role of DYRK1A inhibitors as modulators of β-cells function and suggested a new potential target for antidiabetic therapy. Moreover, we show in detail that leucettine derivatives represent promising antidiabetic agents and are worth further evaluation, especially in vivo.
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Affiliation(s)
- Barbara Pucelik
- Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa, Krakow, Poland
| | - Agata Barzowska
- Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa, Krakow, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University, Krakow, Poland
| | - Anna Czarna
- Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa, Krakow, Poland
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24
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Redhead Y, Gibbins D, Lana-Elola E, Watson-Scales S, Dobson L, Krause M, Liu KJ, Fisher EMC, Green JBA, Tybulewicz VLJ. Craniofacial dysmorphology in Down syndrome is caused by increased dosage of Dyrk1a and at least three other genes. Development 2023; 150:dev201077. [PMID: 37102702 PMCID: PMC10163349 DOI: 10.1242/dev.201077] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 03/21/2023] [Indexed: 04/28/2023]
Abstract
Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), occurs in 1 in 800 live births and is the most common human aneuploidy. DS results in multiple phenotypes, including craniofacial dysmorphology, which is characterised by midfacial hypoplasia, brachycephaly and micrognathia. The genetic and developmental causes of this are poorly understood. Using morphometric analysis of the Dp1Tyb mouse model of DS and an associated mouse genetic mapping panel, we demonstrate that four Hsa21-orthologous regions of mouse chromosome 16 contain dosage-sensitive genes that cause the DS craniofacial phenotype, and identify one of these causative genes as Dyrk1a. We show that the earliest and most severe defects in Dp1Tyb skulls are in bones of neural crest (NC) origin, and that mineralisation of the Dp1Tyb skull base synchondroses is aberrant. Furthermore, we show that increased dosage of Dyrk1a results in decreased NC cell proliferation and a decrease in size and cellularity of the NC-derived frontal bone primordia. Thus, DS craniofacial dysmorphology is caused by an increased dosage of Dyrk1a and at least three other genes.
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Affiliation(s)
- Yushi Redhead
- Centre for Craniofacial Biology and Regenerative Biology, King's College London, London SE1 9RT, UK
- The Francis Crick Institute, London NW1 1AT, UK
| | | | | | | | - Lisa Dobson
- Centre for Craniofacial Biology and Regenerative Biology, King's College London, London SE1 9RT, UK
- Randall Centre for Cell and Molecular Biophysics, King's College London, London SE1 1UL, UK
| | - Matthias Krause
- Randall Centre for Cell and Molecular Biophysics, King's College London, London SE1 1UL, UK
| | - Karen J. Liu
- Centre for Craniofacial Biology and Regenerative Biology, King's College London, London SE1 9RT, UK
| | | | - Jeremy B. A. Green
- Centre for Craniofacial Biology and Regenerative Biology, King's College London, London SE1 9RT, UK
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25
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Stoler-Barak L, Harris E, Peres A, Hezroni H, Kuka M, Di Lucia P, Grenov A, Gurwicz N, Kupervaser M, Yip BH, Iannacone M, Yaari G, Crispino JD, Shulman Z. B cell class switch recombination is regulated by DYRK1A through MSH6 phosphorylation. Nat Commun 2023; 14:1462. [PMID: 36927854 PMCID: PMC10020581 DOI: 10.1038/s41467-023-37205-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 03/06/2023] [Indexed: 03/18/2023] Open
Abstract
Protection from viral infections depends on immunoglobulin isotype switching, which endows antibodies with effector functions. Here, we find that the protein kinase DYRK1A is essential for B cell-mediated protection from viral infection and effective vaccination through regulation of class switch recombination (CSR). Dyrk1a-deficient B cells are impaired in CSR activity in vivo and in vitro. Phosphoproteomic screens and kinase-activity assays identify MSH6, a DNA mismatch repair protein, as a direct substrate for DYRK1A, and deletion of a single phosphorylation site impaired CSR. After CSR and germinal center (GC) seeding, DYRK1A is required for attenuation of B cell proliferation. These findings demonstrate DYRK1A-mediated biological mechanisms of B cell immune responses that may be used for therapeutic manipulation in antibody-mediated autoimmunity.
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Affiliation(s)
- Liat Stoler-Barak
- Department of Systems Immunology, Weizmann Institute of Science, Rehovot, 7610001, Israel
| | - Ethan Harris
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Ayelet Peres
- Faculty of Engineering, Bar Ilan University, Ramat Gan, 52900, Israel
| | - Hadas Hezroni
- Department of Systems Immunology, Weizmann Institute of Science, Rehovot, 7610001, Israel
| | - Mirela Kuka
- Vita-Salute San Raffaele University and Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Pietro Di Lucia
- Vita-Salute San Raffaele University and Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Amalie Grenov
- Department of Systems Immunology, Weizmann Institute of Science, Rehovot, 7610001, Israel
| | - Neta Gurwicz
- Department of Systems Immunology, Weizmann Institute of Science, Rehovot, 7610001, Israel
| | - Meital Kupervaser
- De Botton Institute for Proteomics, Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Bon Ham Yip
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Matteo Iannacone
- Vita-Salute San Raffaele University and Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Gur Yaari
- Faculty of Engineering, Bar Ilan University, Ramat Gan, 52900, Israel
| | - John D Crispino
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Ziv Shulman
- Department of Systems Immunology, Weizmann Institute of Science, Rehovot, 7610001, Israel.
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26
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Yang Y, Fan X, Liu Y, Ye D, Liu C, Yang H, Su Z, Zhang Y, Liu Y. Function and Inhibition of DYRK1A: emerging roles of treating multiple human diseases. Biochem Pharmacol 2023; 212:115521. [PMID: 36990324 DOI: 10.1016/j.bcp.2023.115521] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 03/19/2023] [Accepted: 03/21/2023] [Indexed: 03/30/2023]
Abstract
Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is an evolutionarily conserved protein kinase and the most studied member of the Dual-specificity tyrosine-regulated kinase (DYRK) family. It has been shown that it participates in the development of plenty of diseases, and both the low or high expression of DYRK1A protein could lead to disorder. Thus, DYRK1A is recognized as a key target for the therapy for these diseases, and the studies on natural or synthetic DYRK1A inhibitors have become more and more popular. Here, we provide a comprehensive review for DYRK1A from the structure and function of DYRK1A, the roles of DYRK1A in various types of diseases, including diabetes mellitus, neurodegenerative diseases, and kinds of cancers, and the studies of its natural and synthetic inhibitors.
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27
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Guo Y, Li L, Yao Y, Li H. Regeneration of Pancreatic β-Cells for Diabetes Therapeutics by Natural DYRK1A Inhibitors. Metabolites 2022; 13:metabo13010051. [PMID: 36676976 PMCID: PMC9865674 DOI: 10.3390/metabo13010051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 11/07/2022] [Accepted: 11/23/2022] [Indexed: 12/31/2022] Open
Abstract
The pathogenesis of diabetes mellitus is characterized by insulin resistance and islet β-cell dysfunction. Up to now, the focus of diabetes treatment has been to control blood glucose to prevent diabetic complications. There is an urgent need to develop a therapeutic approach to restore the mass and function of β-cells. Although exogenous islet cell transplantation has been used to help patients control blood glucose, it is costly and has very narrow application scenario. So far, small molecules have been reported to stimulate β-cell proliferation and expand β-cell mass, increasing insulin secretion. Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) inhibitors can induce human β-cell proliferation in vitro and in vivo, and show great potential in the field of diabetes therapeutics. From this perspective, we elaborated on the mechanism by which DYRK1A inhibitors regulate the proliferation of pancreatic β-cells, and summarized several effective natural DYRK1A inhibitors, hoping to provide clues for subsequent structural optimization and drug development in the future.
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Affiliation(s)
- Yichuan Guo
- Institute of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China
| | - Lingqiao Li
- Zhejiang Starry Pharmaceutical Co., Ltd., Taizhou 317306, China
| | - Yuanfa Yao
- Institute of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China
- Correspondence: (Y.Y.); (H.L.)
| | - Hanbing Li
- Institute of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China
- Correspondence: (Y.Y.); (H.L.)
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28
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Krivega M, Stiefel CM, Storchova Z. Consequences of chromosome gain: A new view on trisomy syndromes. Am J Hum Genet 2022; 109:2126-2140. [PMID: 36459979 PMCID: PMC9808507 DOI: 10.1016/j.ajhg.2022.10.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Chromosome gains are detrimental for the development of the human embryo. As such, autosomal trisomies almost always result in spontaneous abortion, and the rare embryos surviving until live birth suffer from a plethora of pathological defects. There is no treatment currently available to ameliorate the consequences of trisomies, such as Down syndrome (trisomy of chromosome 21). Identifying the source of the phenotypes observed in cells with extra chromosomes is crucial for understanding the underlying molecular causes of trisomy syndromes. Although increased expression of the genes localized on the extra chromosome triggers several pathological phenotypes, an alternative model suggests that global, aneuploidy-associated changes in cellular physiology also contribute to the pathology. Here, we compare the molecular consequences of trisomy syndromes in vivo against engineered cell lines carrying various chromosome gains in vitro. We point out several phenotypes that are shared by variable trisomies and, therefore, might be caused by the presence of an extra chromosome per se, independent of its identity. This alternative view may provide useful insights for understanding Down syndrome pathology and open additional opportunities for diagnostics and treatments.
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Affiliation(s)
- Maria Krivega
- Reproduction Genetics, Department of Endocrinology and Infertility Disorders, Women Hospital, Heidelberg University, Im Neuenheimer Feld 440, 69120 Heidelberg, Germany.
| | - Clara M Stiefel
- Department of Radiation Oncology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Zuzana Storchova
- Department of Molecular Genetics, Faculty of Biology, TU Kaiserslautern, Paul-Ehrlich-Str. 24, 67663 Kaiserslautern, Germany
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29
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Deboever E, Fistrovich A, Hulme C, Dunckley T. The Omnipresence of DYRK1A in Human Diseases. Int J Mol Sci 2022; 23:ijms23169355. [PMID: 36012629 PMCID: PMC9408930 DOI: 10.3390/ijms23169355] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/11/2022] [Accepted: 08/17/2022] [Indexed: 01/13/2023] Open
Abstract
The increasing population will challenge healthcare, particularly because the worldwide population has never been older. Therapeutic solutions to age-related disease will be increasingly critical. Kinases are key regulators of human health and represent promising therapeutic targets for novel drug candidates. The dual-specificity tyrosine-regulated kinase (DYRKs) family is of particular interest and, among them, DYRK1A has been implicated ubiquitously in varied human diseases. Herein, we focus on the characteristics of DYRK1A, its regulation and functional role in different human diseases, which leads us to an overview of future research on this protein of promising therapeutic potential.
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Affiliation(s)
- Estelle Deboever
- ASU-Banner Neurodegenerative Disease Research Center, Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA
- Correspondence: (E.D.); (T.D.)
| | - Alessandra Fistrovich
- Department of Chemistry and Biochemistry, College of Science, The University of Arizona, Tucson, AZ 85721, USA
- Division of Drug Discovery and Development, Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA
| | - Christopher Hulme
- Department of Chemistry and Biochemistry, College of Science, The University of Arizona, Tucson, AZ 85721, USA
- Division of Drug Discovery and Development, Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA
| | - Travis Dunckley
- ASU-Banner Neurodegenerative Disease Research Center, Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA
- Correspondence: (E.D.); (T.D.)
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Tumor cell dormancy: Molecular mechanisms, and pharmacological approaches to target dormant cells for countering tumor. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2022.103645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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31
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Wang P, Karakose E, Argmann C, Wang H, Balev M, Brody RI, Rivas HG, Liu X, Wood O, Liu H, Choleva L, Hasson D, Bernstein E, Paulo JA, Scott DK, Lambertini L, DeCaprio JA, Stewart AF. Disrupting the DREAM complex enables proliferation of adult human pancreatic β cells. J Clin Invest 2022; 132:e157086. [PMID: 35700053 PMCID: PMC9337832 DOI: 10.1172/jci157086] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 06/09/2022] [Indexed: 11/17/2022] Open
Abstract
Resistance to regeneration of insulin-producing pancreatic β cells is a fundamental challenge for type 1 and type 2 diabetes. Recently, small molecule inhibitors of the kinase DYRK1A have proven effective in inducing adult human β cells to proliferate, but their detailed mechanism of action is incompletely understood. We interrogated our human insulinoma and β cell transcriptomic databases seeking to understand why β cells in insulinomas proliferate, while normal β cells do not. This search reveals the DREAM complex as a central regulator of quiescence in human β cells. The DREAM complex consists of a module of transcriptionally repressive proteins that assemble in response to DYRK1A kinase activity, thereby inducing and maintaining cellular quiescence. In the absence of DYRK1A, DREAM subunits reassemble into the pro-proliferative MMB complex. Here, we demonstrate that small molecule DYRK1A inhibitors induce human β cells to replicate by converting the repressive DREAM complex to its pro-proliferative MMB conformation.
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Affiliation(s)
- Peng Wang
- Diabetes Obesity Metabolism Institute
- Department of Medicine, and
| | - Esra Karakose
- Diabetes Obesity Metabolism Institute
- Department of Medicine, and
| | - Carmen Argmann
- Department of Genetics and Genomic Sciences, The Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | | | | | - Rachel I. Brody
- Department of Pathology, The Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Hembly G. Rivas
- Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- The Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Xinyue Liu
- Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Olivia Wood
- Diabetes Obesity Metabolism Institute
- Department of Medicine, and
| | - Hongtao Liu
- Diabetes Obesity Metabolism Institute
- Department of Medicine, and
| | - Lauryn Choleva
- Diabetes Obesity Metabolism Institute
- Department of Pediatrics
| | - Dan Hasson
- The Tisch Cancer Institute
- Department of Oncological Sciences
- Bioinformatics for Next Generation Sequencing (BiNGS) Shared Resource Facility, and
| | - Emily Bernstein
- The Tisch Cancer Institute
- Department of Oncological Sciences
- The Graduate School of Biomedical Sciences, The Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Joao A. Paulo
- Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Donald K. Scott
- Diabetes Obesity Metabolism Institute
- Department of Medicine, and
| | - Luca Lambertini
- Diabetes Obesity Metabolism Institute
- Department of Medicine, and
| | - James A. DeCaprio
- Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- The Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Stagni F, Bartesaghi R. The Challenging Pathway of Treatment for Neurogenesis Impairment in Down Syndrome: Achievements and Perspectives. Front Cell Neurosci 2022; 16:903729. [PMID: 35634470 PMCID: PMC9130961 DOI: 10.3389/fncel.2022.903729] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 04/19/2022] [Indexed: 12/17/2022] Open
Abstract
Down syndrome (DS), also known as trisomy 21, is a genetic disorder caused by triplication of Chromosome 21. Gene triplication may compromise different body functions but invariably impairs intellectual abilities starting from infancy. Moreover, after the fourth decade of life people with DS are likely to develop Alzheimer’s disease. Neurogenesis impairment during fetal life stages and dendritic pathology emerging in early infancy are thought to be key determinants of alterations in brain functioning in DS. Although the progressive improvement in medical care has led to a notable increase in life expectancy for people with DS, there are currently no treatments for intellectual disability. Increasing evidence in mouse models of DS reveals that pharmacological interventions in the embryonic and neonatal periods may greatly benefit brain development and cognitive performance. The most striking results have been obtained with pharmacotherapies during embryonic life stages, indicating that it is possible to pharmacologically rescue the severe neurodevelopmental defects linked to the trisomic condition. These findings provide hope that similar benefits may be possible for people with DS. This review summarizes current knowledge regarding (i) the scope and timeline of neurogenesis (and dendritic) alterations in DS, in order to delineate suitable windows for treatment; (ii) the role of triplicated genes that are most likely to be the key determinants of these alterations, in order to highlight possible therapeutic targets; and (iii) prenatal and neonatal treatments that have proved to be effective in mouse models, in order to rationalize the choice of treatment for human application. Based on this body of evidence we will discuss prospects and challenges for fetal therapy in individuals with DS as a potential means of drastically counteracting the deleterious effects of gene triplication.
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Affiliation(s)
- Fiorenza Stagni
- Department for Life Quality Studies, University of Bologna, Rimini, Italy
| | - Renata Bartesaghi
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
- *Correspondence: Renata Bartesaghi,
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Shared Etiology in Autism Spectrum Disorder and Epilepsy with Functional Disability. Behav Neurol 2022; 2022:5893519. [PMID: 35530166 PMCID: PMC9068331 DOI: 10.1155/2022/5893519] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 03/25/2022] [Accepted: 04/01/2022] [Indexed: 11/20/2022] Open
Abstract
Autism spectrum disorders and epilepsies are heterogeneous human disorders that have miscellaneous etiologies and pathophysiology. There is considerable risk of frequent epilepsy in autism that facilitates amplified morbidity and mortality. Several biological pathways appear to be involved in disease progression, including gene transcription regulation, cellular growth, synaptic channel function, and maintenance of synaptic structure. Here, abnormalities in excitatory/inhibitory (E/I) balance ratio are reviewed along with part of an epileptiform activity that may drive both overconnectivity and genetic disorders where autism spectrum disorders and epilepsy frequently co-occur. The most current ideas concerning common etiological and molecular mechanisms for co-occurrence of both autism spectrum disorders and epilepsy are discussed along with the powerful pharmacological therapies that protect the cognition and behavior of patients. Better understanding is necessary to identify a biological mechanism that might lead to possible treatments for these neurological disorders.
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Rammohan M, Harris E, Bhansali RS, Zhao E, Li LS, Crispino JD. The chromosome 21 kinase DYRK1A: emerging roles in cancer biology and potential as a therapeutic target. Oncogene 2022; 41:2003-2011. [PMID: 35220406 PMCID: PMC8977259 DOI: 10.1038/s41388-022-02245-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/02/2022] [Accepted: 02/11/2022] [Indexed: 11/09/2022]
Abstract
Dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) is a serine/threonine kinase that belongs to the DYRK family of proteins, a subgroup of the evolutionarily conserved CMGC protein kinase superfamily. Due to its localization on chromosome 21, the biological significance of DYRK1A was initially characterized in the pathogenesis of Down syndrome (DS) and related neurodegenerative diseases. However, increasing evidence has demonstrated a prominent role in cancer through its ability to regulate biologic processes including cell cycle progression, DNA damage repair, transcription, ubiquitination, tyrosine kinase activity, and cancer stem cell maintenance. DYRK1A has been identified as both an oncogene and tumor suppressor in different models, underscoring the importance of cellular context in its function. Here, we review mechanistic contributions of DYRK1A to cancer biology and its role as a potential therapeutic target.
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Affiliation(s)
- Malini Rammohan
- Driskill Graduate Program in Life Sciences, Northwestern University, Chicago, IL, USA
| | - Ethan Harris
- University of Illinois at Chicago College of Medicine, Chicago, IL, USA
- Division of Experimental Hematology, Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Rahul S Bhansali
- Department of Medicine, Division of Hematology/Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Emily Zhao
- Weinberg College of Arts and Sciences, Northwestern University, Chicago, IL, USA
| | - Loretta S Li
- Molecular and Translational Cancer Biology Program, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
- Department of Pediatrics, Division of Hematology, Oncology, and Stem Cell Transplantation, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - John D Crispino
- Division of Experimental Hematology, Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA.
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Disease Modeling of Rare Neurological Disorders in Zebrafish. Int J Mol Sci 2022; 23:ijms23073946. [PMID: 35409306 PMCID: PMC9000079 DOI: 10.3390/ijms23073946] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 03/31/2022] [Accepted: 03/31/2022] [Indexed: 02/06/2023] Open
Abstract
Rare diseases are those which affect a small number of people compared to the general population. However, many patients with a rare disease remain undiagnosed, and a large majority of rare diseases still have no form of viable treatment. Approximately 40% of rare diseases include neurologic and neurodevelopmental disorders. In order to understand the characteristics of rare neurological disorders and identify causative genes, various model organisms have been utilized extensively. In this review, the characteristics of model organisms, such as roundworms, fruit flies, and zebrafish, are examined, with an emphasis on zebrafish disease modeling in rare neurological disorders.
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El-Gamil DS, ElHady AK, Chen PJ, Hwang TL, Abadi AH, Abdel-Halim M, Engel M. Development of novel conformationally restricted selective Clk1/4 inhibitors through creating an intramolecular hydrogen bond involving an imide linker. Eur J Med Chem 2022; 238:114411. [DOI: 10.1016/j.ejmech.2022.114411] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/20/2022] [Accepted: 04/21/2022] [Indexed: 11/29/2022]
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Zhao L, Xiong X, Liu L, Liang Q, Tong R, Feng X, Bai L, Shi J. Recent research and development of DYRK1A inhibitors. CHINESE CHEM LETT 2022. [DOI: 10.1016/j.cclet.2021.10.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Cell models for Down syndrome-Alzheimer’s disease research. Neuronal Signal 2022; 6:NS20210054. [PMID: 35449591 PMCID: PMC8996251 DOI: 10.1042/ns20210054] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 03/07/2022] [Accepted: 03/21/2022] [Indexed: 11/29/2022] Open
Abstract
Down syndrome (DS) is the most common chromosomal abnormality and leads to intellectual disability, increased risk of cardiac defects, and an altered immune response. Individuals with DS have an extra full or partial copy of chromosome 21 (trisomy 21) and are more likely to develop early-onset Alzheimer’s disease (AD) than the general population. Changes in expression of human chromosome 21 (Hsa21)-encoded genes, such as amyloid precursor protein (APP), play an important role in the pathogenesis of AD in DS (DS-AD). However, the mechanisms of DS-AD remain poorly understood. To date, several mouse models with an extra copy of genes syntenic to Hsa21 have been developed to characterise DS-AD-related phenotypes. Nonetheless, due to genetic and physiological differences between mouse and human, mouse models cannot faithfully recapitulate all features of DS-AD. Cells differentiated from human-induced pluripotent stem cells (iPSCs), isolated from individuals with genetic diseases, can be used to model disease-related cellular and molecular pathologies, including DS. In this review, we will discuss the limitations of mouse models of DS and how these can be addressed using recent advancements in modelling DS using human iPSCs and iPSC-mouse chimeras, and potential applications of iPSCs in preclinical studies for DS-AD.
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Liu T, Wang Y, Wang J, Ren C, Chen H, Zhang J. DYRK1A inhibitors for disease therapy: Current status and perspectives. Eur J Med Chem 2022; 229:114062. [PMID: 34954592 DOI: 10.1016/j.ejmech.2021.114062] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 12/15/2021] [Accepted: 12/17/2021] [Indexed: 02/05/2023]
Abstract
Dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) is a conserved protein kinase that plays essential roles in various biological processes. It is located in the region q22.2 of chromosome 21, which is involved in the pathogenesis of Down syndrome (DS). Moreover, DYRK1A has been shown to promote the accumulation of amyloid beta (Aβ) peptides leading to gradual Tau hyperphosphorylation, which contributes to neurodegeneration. Additionally, alterations in the DRK1A expression are also associated with cancer and diabetes. Recent years have witnessed an explosive increase in the development of DYRK1A inhibitors. A variety of novel DYRK1A inhibitors have been reported as potential treatments for human diseases. In this review, the latest therapeutic potential of DYRK1A for different diseases and the novel DYRK1A inhibitors discoveries are summarized, guiding future inhibitor development and structural optimization.
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Affiliation(s)
- Tong Liu
- Targeted Tracer Research and development laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Institute for Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Yuxi Wang
- Targeted Tracer Research and development laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Institute for Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Jiaxing Wang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, 38163, Tennessee, United States
| | - Changyu Ren
- Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu, Sichuan, 611130, China
| | - Hao Chen
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, 38163, Tennessee, United States
| | - Jifa Zhang
- Targeted Tracer Research and development laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Institute for Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
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Miyazaki Y, Kikuchi M, Umezawa K, Descamps A, Nakamura D, Furuie G, Sumida T, Saito K, Kimura N, Niwa T, Sumida Y, Umehara T, Hosoya T, Kii I. Structure-activity relationship for the folding intermediate-selective inhibition of DYRK1A. Eur J Med Chem 2022; 227:113948. [PMID: 34742017 DOI: 10.1016/j.ejmech.2021.113948] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 10/21/2021] [Accepted: 10/21/2021] [Indexed: 01/06/2023]
Abstract
DYRK1A phosphorylates proteins involved in neurological disorders in an intermolecular manner. Meanwhile, during the protein folding process of DYRK1A, a transitional folding intermediate catalyzes the intramolecular autophosphorylation required for the "one-off" inceptive activation and stabilization. In our previous study, a small molecule termed FINDY (1) was identified, which inhibits the folding intermediate-catalyzed intramolecular autophosphorylation of DYRK1A but not the folded state-catalyzed intermolecular phosphorylation. However, the structural features of FINDY (1) responsible for this intermediate-selective inhibition remain elusive. In this study, structural derivatives of FINDY (1) were designed and synthesized according to its predicted binding mode in the ATP pocket of DYRK1A. Quantitative structure-activity relationship (QSAR) of the derivatives revealed that the selectivity against the folding intermediate is determined by steric hindrance between the bulky hydrophobic moiety of the derivatives and the entrance to the pocket. In addition, a potent derivative 3 was identified, which inhibited the folding intermediate more strongly than FINDY (1); it was designated as dp-FINDY. Although dp-FINDY (3) did not inhibit the folded state, as well as FINDY (1), it inhibited the intramolecular autophosphorylation of DYRK1A in an in vitro cell-free protein synthesis assay. Furthermore, dp-FINDY (3) destabilized endogenous DYRK1A in HEK293 cells. This study provides structural insights into the folding intermediate-selective inhibition of DYRK1A and expands the chemical options for the design of a kinase inhibitor.
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Affiliation(s)
- Yuka Miyazaki
- Laboratory for Drug Target Research, Department of Agriculture, Graduate School of Science and Technology, Shinshu University, 8304 Minami-Minowa, Kami-Ina, Nagano, 399-4598, Japan
| | - Masaki Kikuchi
- Laboratory for Epigenetics Drug Discovery, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan
| | - Koji Umezawa
- Department of Biomolecular Innovation, Institute for Biomedical Sciences, Shinshu University, 8304 Minami-Minowa, Kami-Ina, Nagano, 399-4598, Japan
| | - Aurelie Descamps
- Laboratory for Chemical Biology, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Daichi Nakamura
- Laboratory for Chemical Biology, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Gaku Furuie
- Laboratory for Drug Target Research, Department of Agriculture, Graduate School of Science and Technology, Shinshu University, 8304 Minami-Minowa, Kami-Ina, Nagano, 399-4598, Japan
| | - Tomoe Sumida
- Laboratory for Chemical Biology, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Kanako Saito
- Laboratory for Drug Target Research, Department of Agriculture, Graduate School of Science and Technology, Shinshu University, 8304 Minami-Minowa, Kami-Ina, Nagano, 399-4598, Japan
| | - Ninako Kimura
- Laboratory for Drug Target Research, Department of Agriculture, Graduate School of Science and Technology, Shinshu University, 8304 Minami-Minowa, Kami-Ina, Nagano, 399-4598, Japan
| | - Takashi Niwa
- Laboratory for Chemical Biology, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Yuto Sumida
- Laboratory for Chemical Biology, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Takashi Umehara
- Laboratory for Epigenetics Drug Discovery, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan
| | - Takamitsu Hosoya
- Laboratory for Chemical Biology, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan; Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo, 101-0062, Japan
| | - Isao Kii
- Laboratory for Drug Target Research, Department of Agriculture, Graduate School of Science and Technology, Shinshu University, 8304 Minami-Minowa, Kami-Ina, Nagano, 399-4598, Japan; Department of Biomolecular Innovation, Institute for Biomedical Sciences, Shinshu University, 8304 Minami-Minowa, Kami-Ina, Nagano, 399-4598, Japan; Laboratory for Chemical Biology, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan.
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AlNajjar YT, Gabr M, ElHady AK, Salah M, Wilms G, Abadi AH, Becker W, Abdel-Halim M, Engel M. Discovery of novel 6-hydroxybenzothiazole urea derivatives as dual Dyrk1A/α-synuclein aggregation inhibitors with neuroprotective effects. Eur J Med Chem 2022; 227:113911. [PMID: 34710745 DOI: 10.1016/j.ejmech.2021.113911] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 10/04/2021] [Accepted: 10/06/2021] [Indexed: 12/20/2022]
Abstract
A role of Dyrk1A in the progression of Down syndrome-related Alzheimer's disease (AD) is well supported. However, the involvement of Dyrk1A in the pathogenesis of Parkinson's disease (PD) was much less studied, and it is not clear whether it would be promising to test Dyrk1A inhibitors in relevant PD models. Herein, we modified our previously published 1-(6-hydroxybenzo[d]thiazol-2-yl)-3-phenylurea scaffold of Dyrk1A inhibitors to obtain a new series of analogues with higher selectivity for Dyrk1A on the one hand, but also with a novel, additional activity as inhibitors of α-synuclein (α-syn) aggregation, a major pathogenic hallmark of PD. The phenyl acetamide derivative b27 displayed the highest potency against Dyrk1A with an IC50 of 20 nM and high selectivity over closely related kinases. Furthermore, b27 was shown to successfully target intracellular Dyrk1A and to inhibit SF3B1 phosphorylation in HeLa cells with an IC50 of 690 nM. In addition, two compounds among the Dyrk1A inhibitors, b1 and b20, also suppressed the aggregation of α-synuclein (α-syn) oligomers (with IC50 values of 10.5 μM and 7.8 μM, respectively). Both compounds but not the Dyrk1A reference inhibitor harmine protected SH-SY5Y neuroblastoma cells against α-syn-induced cytotoxicity, with b20 exhibiting a higher neuroprotective effect. Compound b1 and harmine were more efficient in protecting SH-SY5Y cells against 6-hydroxydopamine-induced cell death, an effect that was previously correlated to Dyrk1A inactivation in cells but not yet verified using chemical inhibitors. The presented dual inhibitors exhibited a novel activity profile encouraging for further testing in neurodegenerative disease models.
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Affiliation(s)
- Yasmeen T AlNajjar
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, 11835, Egypt
| | - Moustafa Gabr
- Department of Radiology, Stanford University, CA, 94305, United States
| | - Ahmed K ElHady
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, 11835, Egypt; School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, New Administrative Capital, Cairo, Egypt
| | - Mohamed Salah
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, October University for Modern Sciences and Arts, Cairo, 12451, Egypt
| | - Gerrit Wilms
- Institute of Pharmacology and Toxicology, Medical Faculty of the RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany
| | - Ashraf H Abadi
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, 11835, Egypt
| | - Walter Becker
- Institute of Pharmacology and Toxicology, Medical Faculty of the RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany
| | - Mohammad Abdel-Halim
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, 11835, Egypt.
| | - Matthias Engel
- Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, D-66123, Saarbrücken, Germany.
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New insights into the roles for DYRK family in mammalian development and congenital diseases. Genes Dis 2022. [DOI: 10.1016/j.gendis.2021.12.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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Coulonval K, Vercruysse V, Paternot S, Pita JM, Corman R, Raspé E, Roger PP. Monoclonal antibodies to activated CDK4: use to investigate normal and cancerous cell cycle regulation and involvement of phosphorylations of p21 and p27. Cell Cycle 2021; 21:12-32. [PMID: 34913830 PMCID: PMC8837260 DOI: 10.1080/15384101.2021.1984663] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Cyclin-dependent kinase 4 (CDK4) is a master integrator that couples mitogenic/oncogenic signaling with the cell division cycle. It is deregulated in most cancers and inhibitors of CDK4 have become standard of care drugs for metastatic estrogen-receptor positive breast cancers and are being evaluated in a variety of other cancers. We previously characterized the T-loop phosphorylation at T172 of CDK4 as the highly regulated step that determines the activity of cyclin D-CDK4 complexes. Moreover we demonstrated that the highly variable detection of T172-phosphorylated CDK4 signals the presence or absence of the active CDK4 targeted by the CDK4/6 inhibitory drugs, which predicts the tumor cell sensitivity to these drugs including palbociclib. To date, the phosphorylation of CDK4 has been very poorly studied because only few biochemical techniques and reagents are available for it. In addition, the available ones including 2D-IEF separation of CDK4 modified forms are considered too tedious. The present report describes the generation, selection and characterization of the first monoclonal antibodies that specifically recognize the active CDK4 phosphorylated on its T172 residue. One key to this success was the immunization with a long phosphopeptide corresponding to the complete activation segment of CDK4. These monoclonal antibodies specifically recognize T172-phosphorylated CDK4 in a variety of assays, including western blotting, immunoprecipitation and, as a capture antibody, a sensitive ELISA from cell lysates. The specific immunoprecipitation of T172-phosphorylated CDK4 allowed to clarify the involvement of phosphorylations of co-immunoprecipitated p21 and p27, showing a privileged interaction of T172-phosphorylated CDK4 with S130-phosphorylated p21 and S10-phosphorylated p27.
Abbreviations:
2D: two-dimensional; CAK: CDK-activating kinase; CDK: cyclin-dependent kinase; HAT: Hypoxanthine-Aminopterin-Thymidine; FBS: fetal bovine serum; IP: immunoprecipitation; ID: immunodetection; mAb: monoclonal antibody; PAGE: polyacrylamide gel electrophoresis; PBS: phosphate buffer saline; pRb: retinoblastoma susceptibility protein; SDS: sodium dodecyl sulfate; DTT: dithiotreitol; TET: tetracyclin repressor; Avi: Avi tag; TEV: tobacco etch virus cleavage site; EGFP: enhanced green fluorescent protein; BirA: bifunctional protein biotin ligase BirA; IRES: internal ribosome entry site; HIS: poly-HIS purification tag; DELFIA: dissociation-enhanced lanthanide fluorescent immunoassay; 3-MBPP1: 1-(1,1-dimethylethyl)-3[(3-methylphenyl) methyl]-1H-pyrazolo[3,4-d] pyrimidin-4-amine; BSA: bovine serum albumin; ECL: Enhanced chemiluminescence
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Affiliation(s)
- Katia Coulonval
- Institute of Interdisciplinary Research (Iribhm) and ULB-Cancer Research Center (U-crc), Université Libre de Bruxelles, Campus Erasme, Brussels, Belgium
| | - Vincent Vercruysse
- Institute of Interdisciplinary Research (Iribhm) and ULB-Cancer Research Center (U-crc), Université Libre de Bruxelles, Campus Erasme, Brussels, Belgium
| | - Sabine Paternot
- Institute of Interdisciplinary Research (Iribhm) and ULB-Cancer Research Center (U-crc), Université Libre de Bruxelles, Campus Erasme, Brussels, Belgium
| | - Jaime M Pita
- Institute of Interdisciplinary Research (Iribhm) and ULB-Cancer Research Center (U-crc), Université Libre de Bruxelles, Campus Erasme, Brussels, Belgium
| | - Robert Corman
- Kaneka Eurogentec, Liège Science Park, Seraing, Belgium
| | - Eric Raspé
- Institute of Interdisciplinary Research (Iribhm) and ULB-Cancer Research Center (U-crc), Université Libre de Bruxelles, Campus Erasme, Brussels, Belgium
| | - Pierre P Roger
- Institute of Interdisciplinary Research (Iribhm) and ULB-Cancer Research Center (U-crc), Université Libre de Bruxelles, Campus Erasme, Brussels, Belgium
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Atas-Ozcan H, Brault V, Duchon A, Herault Y. Dyrk1a from Gene Function in Development and Physiology to Dosage Correction across Life Span in Down Syndrome. Genes (Basel) 2021; 12:1833. [PMID: 34828439 PMCID: PMC8624927 DOI: 10.3390/genes12111833] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/15/2021] [Accepted: 11/18/2021] [Indexed: 01/12/2023] Open
Abstract
Down syndrome is the main cause of intellectual disabilities with a large set of comorbidities from developmental origins but also that appeared across life span. Investigation of the genetic overdosage found in Down syndrome, due to the trisomy of human chromosome 21, has pointed to one main driver gene, the Dual-specificity tyrosine-regulated kinase 1A (Dyrk1a). Dyrk1a is a murine homolog of the drosophila minibrain gene. It has been found to be involved in many biological processes during development and in adulthood. Further analysis showed its haploinsufficiency in mental retardation disease 7 and its involvement in Alzheimer's disease. DYRK1A plays a role in major developmental steps of brain development, controlling the proliferation of neural progenitors, the migration of neurons, their dendritogenesis and the function of the synapse. Several strategies targeting the overdosage of DYRK1A in DS with specific kinase inhibitors have showed promising evidence that DS cognitive conditions can be alleviated. Nevertheless, providing conditions for proper temporal treatment and to tackle the neurodevelopmental and the neurodegenerative aspects of DS across life span is still an open question.
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Affiliation(s)
- Helin Atas-Ozcan
- Université de Strasbourg, CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France; (H.A.-O.); (V.B.); (A.D.)
| | - Véronique Brault
- Université de Strasbourg, CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France; (H.A.-O.); (V.B.); (A.D.)
| | - Arnaud Duchon
- Université de Strasbourg, CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France; (H.A.-O.); (V.B.); (A.D.)
| | - Yann Herault
- Université de Strasbourg, CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France; (H.A.-O.); (V.B.); (A.D.)
- Université de Strasbourg, CNRS, INSERM, Celphedia, Phenomin-Institut Clinique de la Souris (ICS), 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France
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Aboushady Y, Gabr M, ElHady AK, Salah M, Abadi AH, Wilms G, Becker W, Abdel-Halim M, Engel M. Discovery of Hydroxybenzothiazole Urea Compounds as Multitargeted Agents Suppressing Major Cytotoxic Mechanisms in Neurodegenerative Diseases. ACS Chem Neurosci 2021; 12:4302-4318. [PMID: 34726394 DOI: 10.1021/acschemneuro.1c00475] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Multiple factors are causally responsible and/or contribute to the progression of Alzheimer's and Parkinson's diseases. The protein kinase Dyrk1A was identified as a promising target as it phosphorylates tau protein, α-synuclein, and parkin. The first goal of our study was to optimize our previously identified Dyrk1A inhibitors of the 6-hydroxy benzothiazole urea chemotype in terms of potency and selectivity. Our efforts led to the development of the 3-fluorobenzyl amide derivative 16b, which displayed the highest potency against Dyrk1A (IC50 = 9.4 nM). In general, the diversification of the benzylamide moiety led to an enhanced selectivity over the most homologous isoform, Dyrk1B, which was a meaningful indicator, as the high selectivity could be confirmed in an extended selectivity profiling of 3b and 16b. Eventually, we identified the novel phenethyl amide derivative 24b as a triple inhibitor of Dyrk1A kinase activity (IC50 = 119 nM) and the aggregation of tau and α-syn oligomers. We provide evidence that the novel combination of selective Dyrk1A inhibition and suppression of tau and α-syn aggregations of our new lead compound confers efficacy in several established cellular models of neurotoxic mechanisms relevant to neurodegenerative diseases, including α-syn- and 6-hydroxydopamine-induced cytotoxicities.
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Affiliation(s)
- Youssef Aboushady
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
| | - Moustafa Gabr
- Department of Radiology, Stanford University, Stanford, California 94305, United States
| | - Ahmed K. ElHady
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
- School of Life and Medical Sciences, University of Hertfordshire Hosted By Global Academic Foundation, New Administrative Capital, Cairo 11311, Egypt
| | - Mohamed Salah
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, October University for Modern Sciences and Arts, Cairo 12451, Egypt
| | - Ashraf H. Abadi
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
| | - Gerrit Wilms
- Institute of Pharmacology and Toxicology, Medical Faculty of the RWTH Aachen University, Wendlingweg 2, Aachen 52074, Germany
| | - Walter Becker
- Institute of Pharmacology and Toxicology, Medical Faculty of the RWTH Aachen University, Wendlingweg 2, Aachen 52074, Germany
| | - Mohammad Abdel-Halim
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
| | - Matthias Engel
- Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3 Saarbrücken D-66123, Germany
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Massey AJ, Benwell K, Burbridge M, Kotschy A, Walmsley DL. Targeting DYRK1A/B kinases to modulate p21-cyclin D1-p27 signalling and induce anti-tumour activity in a model of human glioblastoma. J Cell Mol Med 2021; 25:10650-10662. [PMID: 34708541 PMCID: PMC8581321 DOI: 10.1111/jcmm.17002] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 09/08/2021] [Accepted: 09/30/2021] [Indexed: 12/24/2022] Open
Abstract
The dual-specificity tyrosine-regulated kinases DYRK1A and DYRK1B play a key role in controlling the quiescence-proliferation switch in cancer cells. Serum reduction of U87MG 2D cultures or multi-cellular tumour spheroids induced a quiescent like state characterized by increased DYRK1B and p27, and decreased pRb and cyclin D1. VER-239353 is a potent, selective inhibitor of the DYRK1A and DYRK1B kinases identified through fragment and structure-guided drug discovery. Inhibition of DYRK1A/B by VER-239353 in quiescent U87MG cells increased pRb, DYRK1B and cyclin D1 but also increased the cell cycle inhibitors p21 and p27. This resulted in exit from G0 but subsequent arrest in G1. DYRK1A/B inhibition reduced the proliferation of U87MG cells in 2D and 3D culture with greater effects observed under reduced serum conditions. Paradoxically, the induced re-expression of cell cycle proteins by DYRK1A/B inhibition further inhibited cell proliferation. Cell growth arrest induced in quiescent cells by DYRK1A/B inhibition was reversible through the addition of growth-promoting factors. DYRK inhibition-induced DNA damage and synergized with a CHK1 inhibitor in the U87MG spheroids. In vivo, DYRK1A/B inhibition-induced tumour stasis in a U87MG tumour xenograft model. These results suggest that further evaluation of VER-239353 as a treatment for glioblastoma is therefore warranted.
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Affiliation(s)
| | | | - Mike Burbridge
- Institut de Recherches ServierCroissy‐sur‐SeineFrance
- Present address:
EngitixLondonUK
| | - Andras Kotschy
- Servier Research Institute of Medicinal ChemistryBudapestHungary
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Choi M, Kim AK, Ham Y, Lee JY, Kim D, Yang A, Jo MJ, Yoon E, Heo JN, Han SB, Ki MH, Lee KS, Cho S. Aristolactam BIII, a naturally derived DYRK1A inhibitor, rescues Down syndrome-related phenotypes. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 92:153695. [PMID: 34500300 DOI: 10.1016/j.phymed.2021.153695] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 07/28/2021] [Accepted: 07/30/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a significant pathogenic factor in Down syndrome (DS), wherein DYRK1A is overexpressed by 1.5-fold because of trisomy of human chromosome 21. Thus, DYRK1A inhibition is considered a therapeutic strategy to modify the disease. PURPOSE This study aims to identify a novel DYRK1A inhibitor and validate its therapeutic potential in DS-related pathological conditions. STUDY DESIGN In order to identify a novel DYRK1A inhibitor, we carried out two-step screening: a structure-based virtual screening of > 300,000 chemical library (first step) and cell-based nuclear factor of activated T-cells (NFAT)-response element (RE) promoter assay (second step). Primary hits were evaluated for their DYRK1A inhibitory activity using in vitro kinase assay and Tau phosphorylation in mammalian cells. Confirmed hit was further evaluated in pathological conditions including DYRK1A-overexpressing fibroblasts, flies, and mice. RESULTS We identified aristolactam BIII, a natural product derived from herbal plants, as a novel DYRK1A inhibitor. It potently inhibited the kinase activity of DYRK1A in vitro (IC50 = 9.67 nM) and effectively suppressed DYRK1A-mediated hyperphosphorylation of Tau in mammalian cells. Aristolactam BIII rescued the proliferative defects of DYRK1A transgenic (TG) mouse-derived fibroblasts and neurological and phenotypic defects of DS-like Drosophila models. Oral administration of aristolactam BIII acutely suppressed Tau hyperphosphorylation in the brain of DYRK1A TG mice. In the open field test, aristolactam BIII significantly ameliorated the exploratory behavioral deficit of DYRK1A TG mice. CONCLUSION Our work revealed that aristolactam BIII as a novel DYRK1A inhibitor rescues DS phenotypes in cells and in vivo and suggested its therapeutic potential for the treatment of DYRK1A-related diseases.
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Affiliation(s)
- Miri Choi
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju-si, Chungbuk 28116, Republic of Korea; College of Pharmacy, Chungbuk National University, 30-1 Yeonje-ri, Osong-eup, Heungduk-gu, Cheongju-si, Chungbuk 28644, Republic of Korea
| | - Ae-Kyeong Kim
- Bionanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea
| | - Youngwook Ham
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju-si, Chungbuk 28116, Republic of Korea; Department of Biomolecular Science, KRIBB School of Bioscience, Korea University of Science and Technology, 217, Gajeong-ro, Yuseong-gu, Daejeon 34113, Republic of Korea
| | - Joo-Youn Lee
- Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Jang-dong, Yuseong-gu, Daejeon 34114, Republic of Korea
| | - Daeyong Kim
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju-si, Chungbuk 28116, Republic of Korea; Department of Biomolecular Science, KRIBB School of Bioscience, Korea University of Science and Technology, 217, Gajeong-ro, Yuseong-gu, Daejeon 34113, Republic of Korea
| | - Ansook Yang
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju-si, Chungbuk 28116, Republic of Korea; College of Pharmacy, Chungbuk National University, 30-1 Yeonje-ri, Osong-eup, Heungduk-gu, Cheongju-si, Chungbuk 28644, Republic of Korea
| | - Min Ju Jo
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju-si, Chungbuk 28116, Republic of Korea; College of Pharmacy, Chungbuk National University, 30-1 Yeonje-ri, Osong-eup, Heungduk-gu, Cheongju-si, Chungbuk 28644, Republic of Korea
| | - Eunyoung Yoon
- Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Jang-dong, Yuseong-gu, Daejeon 34114, Republic of Korea
| | - Jung-Nyoung Heo
- Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Jang-dong, Yuseong-gu, Daejeon 34114, Republic of Korea
| | - Sang-Bae Han
- College of Pharmacy, Chungbuk National University, 30-1 Yeonje-ri, Osong-eup, Heungduk-gu, Cheongju-si, Chungbuk 28644, Republic of Korea
| | - Min-Hyo Ki
- Center Research Institute, Samjin Pharm. Co., Ltd., 16, Daewangpangyo-ro 712 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi 13488, Republic of Korea
| | - Kyu-Sun Lee
- Bionanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea
| | - Sungchan Cho
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju-si, Chungbuk 28116, Republic of Korea; Department of Biomolecular Science, KRIBB School of Bioscience, Korea University of Science and Technology, 217, Gajeong-ro, Yuseong-gu, Daejeon 34113, Republic of Korea.
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p27 Kip1, an Intrinsically Unstructured Protein with Scaffold Properties. Cells 2021; 10:cells10092254. [PMID: 34571903 PMCID: PMC8465030 DOI: 10.3390/cells10092254] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/21/2021] [Accepted: 08/24/2021] [Indexed: 12/27/2022] Open
Abstract
The Cyclin-dependent kinase (CDK) regulator p27Kip1 is a gatekeeper of G1/S transition. It also regulates G2/M progression and cytokinesis completion, via CDK-dependent or -independent mechanisms. Recently, other important p27Kip1 functions have been described, including the regulation of cell motility and migration, the control of cell differentiation program and the activation of apoptosis/autophagy. Several factors modulate p27Kip1 activities, including its level, cellular localization and post-translational modifications. As a matter of fact, the protein is phosphorylated, ubiquitinated, SUMOylated, O-linked N-acetylglicosylated and acetylated on different residues. p27Kip1 belongs to the family of the intrinsically unstructured proteins and thus it is endowed with a large flexibility and numerous interactors, only partially identified. In this review, we look at p27Kip1 properties and ascribe part of its heterogeneous functions to the ability to act as an anchor or scaffold capable to participate in the construction of different platforms for modulating cell response to extracellular signals and allowing adaptation to environmental changes.
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Sato K, Padgaonkar AA, Baker SJ, Cosenza SC, Rechkoblit O, Subbaiah DRCV, Domingo-Domenech J, Bartkowski A, Port ER, Aggarwal AK, Ramana Reddy MV, Irie HY, Reddy EP. Simultaneous CK2/TNIK/DYRK1 inhibition by 108600 suppresses triple negative breast cancer stem cells and chemotherapy-resistant disease. Nat Commun 2021; 12:4671. [PMID: 34344863 PMCID: PMC8333338 DOI: 10.1038/s41467-021-24878-z] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 07/08/2021] [Indexed: 02/07/2023] Open
Abstract
Triple negative breast cancer (TNBC) remains challenging because of heterogeneous responses to chemotherapy. Incomplete response is associated with a greater risk of metastatic progression. Therefore, treatments that target chemotherapy-resistant TNBC and enhance chemosensitivity would improve outcomes for these high-risk patients. Breast cancer stem cell-like cells (BCSCs) have been proposed to represent a chemotherapy-resistant subpopulation responsible for tumor initiation, progression and metastases. Targeting this population could lead to improved TNBC disease control. Here, we describe a novel multi-kinase inhibitor, 108600, that targets the TNBC BCSC population. 108600 treatment suppresses growth, colony and mammosphere forming capacity of BCSCs and induces G2M arrest and apoptosis of TNBC cells. In vivo, 108600 treatment of mice bearing triple negative tumors results in the induction of apoptosis and overcomes chemotherapy resistance. Finally, treatment with 108600 and chemotherapy suppresses growth of pre-established TNBC metastases, providing additional support for the clinical translation of this agent to clinical trials.
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Affiliation(s)
- Katsutoshi Sato
- Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Amol A Padgaonkar
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Stacey J Baker
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Stephen C Cosenza
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Olga Rechkoblit
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - D R C Venkata Subbaiah
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Alison Bartkowski
- Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Elisa R Port
- Department of Surgery, Mount Sinai Hospital, New York, NY, USA
| | - Aneel K Aggarwal
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - M V Ramana Reddy
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Hanna Y Irie
- Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - E Premkumar Reddy
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Ghosh A, Singh S. Regulation Of Microtubule: Current Concepts And Relevance To Neurodegenerative Diseases. CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS 2021; 21:656-679. [PMID: 34323203 DOI: 10.2174/1871527320666210728144043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 01/05/2021] [Accepted: 02/23/2021] [Indexed: 11/22/2022]
Abstract
Neurodevelopmental disorders (NDDs) are abnormalities linked to neuronal structure and irregularities associated with the proliferation of cells, transportation, and differentiation. NDD also involves synaptic circuitry and neural network alterations known as synaptopathies. Microtubules (MTs) and MTs-associated proteins help to maintain neuronal health as well as their development. The microtubular dynamic structure plays a crucial role in the division of cells and forms mitotic spindles, thus take part in initiating stages of differentiation and polarization for various types of cells. The MTs also take part in the cellular death but MT-based cellular degenerations are not yet well excavated. In the last few years, studies have provided the protagonist activity of MTs in neuronal degeneration. In this review, we largely engrossed our discussion on the change of MT cytoskeleton structure, describing their organization, dynamics, transportation, and their failure causing NDDs. At end of this review, we are targeting the therapeutic neuroprotective strategies on clinical priority and also try to discuss the clues for the development of new MT-based therapy as a new pharmacological intervention. This will be a new potential site to block not only neurodegeneration but also promotes the regeneration of neurons.
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Affiliation(s)
- Anirban Ghosh
- Neuroscience Division, Department of Pharmacology, ISF College of Pharmacy, Moga-142001 Punjab, India
| | - Shamsher Singh
- Neuroscience Division, Department of Pharmacology, ISF College of Pharmacy, Moga-142001 Punjab, India
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