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Chaudhury S, D'Amico T, Blagg BSJ. The Hsp90β Isoform: An Attractive Target for Drug Development. Med Res Rev 2025. [PMID: 40293270 DOI: 10.1002/med.22114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 02/12/2025] [Accepted: 04/09/2025] [Indexed: 04/30/2025]
Abstract
The beta isoform of 90 kDa heat shock protein (Hsp90β) plays a critical role in maintaining cellular proteostasis by assisting in the folding and refolding of proteins, which is essential for both normal cellular function and stress response. It is constitutively expressed in mammalian cells, differentiating it from the inducible Hsp90α isoform. Hsp90β's involvement in diverse cellular processes, such as signal transduction, cell cycle control, and apoptosis, underscores its significant role in various diseases, including cancer and neurodegenerative disorders. The isoform-specific functions of Hsp90β and its interaction with unique client proteins make it a promising target for therapeutic intervention, particularly in the development of selective inhibitors that avoid the adverse effects observed with pan-Hsp90 inhibitors. This review delves into the structural and functional intricacies of Hsp90β, its role in disease, and the potential for selective drug development.
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Affiliation(s)
- Subhabrata Chaudhury
- Department of Chemistry and Biochemistry, Warren Family Research Center for Drug Discovery and Development, University of Notre Dame, Notre Dame, Indiana, USA
| | - Terin D'Amico
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA
| | - Brian S J Blagg
- Department of Chemistry and Biochemistry, Warren Family Research Center for Drug Discovery and Development, University of Notre Dame, Notre Dame, Indiana, USA
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2
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Ehrenberg M, Avraham M, Asodu SS, Moye AR, Sangermano R, Rizel L, Ali-Nasser T, Sher I, Gurwitz D, Chao KR, Rivera A, Webster AR, Rivolta C, Newman H, Pras E, Rotenstreich Y, Banin E, Pierce EA, Zur D, Arno G, Bujakowska KM, Lin S, Sharon D, Ben-Yosef T. Biallelic null variants in C19orf44 cause a unique late-onset retinal dystrophy phenotype characterized by patchy perifoveal chorioretinal atrophy. Genet Med 2025; 27:101401. [PMID: 40079362 DOI: 10.1016/j.gim.2025.101401] [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: 08/27/2024] [Revised: 02/25/2025] [Accepted: 02/25/2025] [Indexed: 03/15/2025] Open
Abstract
PURPOSE To identify the genetic cause for disease in individuals affected with inherited retinal disease and to characterize their retinal phenotype and the properties of the underlying gene. METHODS Participants underwent a comprehensive ophthalmological evaluation, including best-corrected visual acuity, visual field testing, fundus autofluorescence, optical coherence tomography, and electroretinography. Genetic analyses included exome, genome, and Sanger sequencing. Gene expression pattern was analyzed by reverse transcription-polymerase chain reaction. Localization of the encoded protein in cells and in the human retina was examined by immunofluorescence staining. RESULTS Four different pathogenic variants in C19orf44 were identified in 15 biallelic individuals from 11 unrelated families. The most common variant was c.549_550del p.(Ser185ProfsTer2). Most individuals were affected with a unique clinical phenotype characterized by late-onset patchy perifoveal chorioretinal atrophy and electroretinographic features of rod-cone degeneration. C19orf44 is expressed in various human tissues, including the retina, where it was found in the outer nuclear layer and in the outer plexiform layer. In cultured cells (hTERT RPE-1 and HeLa) and in human primary fibroblasts, C19orf44 is found in the nucleus, and it is downregulated during mitosis. CONCLUSION Based on our results, C19orf44 is crucial for normal human retinal function, and pathogenic variants in this gene are associated with autosomal recessive inherited retinal disease.
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Affiliation(s)
- Miriam Ehrenberg
- Department of Ophthalmology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel; Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Maayan Avraham
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Sandeep Sarma Asodu
- Division of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Abigail R Moye
- Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland; Department of Ophthalmology, University Hospital Basel, Basel, Switzerland
| | - Riccardo Sangermano
- Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA
| | - Leah Rizel
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Tahleel Ali-Nasser
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Ifat Sher
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel; Goldschleger Eye Institute, Sheba Medical Center, Tel Hashomer, Israel
| | - David Gurwitz
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel; Sagol School for Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Katherine R Chao
- Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA
| | - Antonio Rivera
- Division of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Andrew R Webster
- National Institute of Health Research Biomedical Research Centre at Moorfields Eye Hospital and The Institute of Ophthalmology, London, United Kingdom; Institute of Ophthalmology, University College London, London, United Kingdom
| | - Carlo Rivolta
- Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland; Department of Ophthalmology, University Hospital Basel, Basel, Switzerland; Department of Genetics and Genome Biology, University of Leicester, Leicester, United Kingdom
| | - Hadas Newman
- Division of Ophthalmology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Eran Pras
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel; Ophthalmology Department, Shamir Medical Center, Zerifin, Israel
| | - Ygal Rotenstreich
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel; Goldschleger Eye Institute, Sheba Medical Center, Tel Hashomer, Israel; Sagol School for Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Eyal Banin
- Division of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Eric A Pierce
- Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA
| | - Dinah Zur
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel; Division of Ophthalmology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Gavin Arno
- National Institute of Health Research Biomedical Research Centre at Moorfields Eye Hospital and The Institute of Ophthalmology, London, United Kingdom; Institute of Ophthalmology, University College London, London, United Kingdom; Greenwood Genetic Center, Greenwood, SC
| | - Kinga M Bujakowska
- Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA
| | - Siying Lin
- National Institute of Health Research Biomedical Research Centre at Moorfields Eye Hospital and The Institute of Ophthalmology, London, United Kingdom; Institute of Ophthalmology, University College London, London, United Kingdom
| | - Dror Sharon
- Division of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Tamar Ben-Yosef
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
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Rahmé R, Resnick-Silverman L, Anguiano V, Campbell MJ, Fenaux P, Manfredi JJ. Mutant p53 regulates a distinct gene set by a mode of genome occupancy that is shared with wild type. EMBO Rep 2025; 26:1315-1343. [PMID: 39875582 PMCID: PMC11893899 DOI: 10.1038/s44319-025-00375-y] [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: 07/28/2023] [Revised: 01/05/2025] [Accepted: 01/14/2025] [Indexed: 01/30/2025] Open
Abstract
To directly examine the interplay between mutant p53 or Mdm2 and wild type p53 in gene occupancy and expression, an integrated RNA-seq and ChIP-seq analysis was performed in vivo using isogenically matched mouse strains. Response to radiation was used as an endpoint to place findings in a biologically relevant context. Unexpectedly, mutant p53 and Mdm2 only inhibit a subset of wild type p53-mediated gene expression. In contrast to a dominant-negative or inhibitory role, the presence of either mutant p53 or Mdm2 actually enhances the occupancy of wild type p53 on many canonical targets. The C-terminal 19 amino acids of wild type p53 suppress the p53 response allowing for survival at sublethal doses of radiation. Further, the p53 mutant 172H is shown to occupy genes and regulate their expression via non-canonical means that are shared with wild type p53. This results in the heterozygous 172H/+ genotype having an expanded transcriptome compared to wild type p53 + /+.
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Affiliation(s)
- Ramy Rahmé
- Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Institut de Recherche Saint Louis (IRSL), INSERM U1131, Université de Paris, Paris, France
- Ecole Doctorale Hématologie-Oncogenèse-Biothérapies, Université de Paris, Paris, France
| | - Lois Resnick-Silverman
- Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Vincent Anguiano
- Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | | | - Pierre Fenaux
- Institut de Recherche Saint Louis (IRSL), INSERM U1131, Université de Paris, Paris, France
- Service Hématologie Seniors, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris (AP-HP), Université de Paris, Paris, France
| | - James J Manfredi
- Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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Elfar G, Aning O, Ngai T, Yeo P, Chan J, Sim S, Goh L, Yuan J, Phua C, Yeo J, Mak S, Goh B, Chow PH, Tam W, Ho Y, Cheok C. p53-dependent crosstalk between DNA replication integrity and redox metabolism mediated through a NRF2-PARP1 axis. Nucleic Acids Res 2024; 52:12351-12377. [PMID: 39315696 PMCID: PMC11551750 DOI: 10.1093/nar/gkae811] [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: 02/01/2024] [Revised: 08/24/2024] [Accepted: 09/10/2024] [Indexed: 09/25/2024] Open
Abstract
Mechanisms underlying p53-mediated protection of the replicating genome remain elusive, despite the quintessential role of p53 in maintaining genomic stability. Here, we uncover an unexpected function of p53 in curbing replication stress by limiting PARP1 activity and preventing the unscheduled degradation of deprotected stalled forks. We searched for p53-dependent factors and elucidated RRM2B as a prime factor. Deficiency in p53/RRM2B results in the activation of an NRF2 antioxidant transcriptional program, with a concomitant elevation in basal PARylation in cells. Dissecting the consequences of p53/RRM2B loss revealed a crosstalk between redox metabolism and genome integrity that is negotiated through a hitherto undescribed NRF2-PARP1 axis, and pinpoint G6PD as a primary oxidative stress-induced NRF2 target and activator of basal PARylation. This study elucidates how loss of p53 could be destabilizing for the replicating genome and, importantly, describes an unanticipated crosstalk between redox metabolism, PARP1 and p53 tumor suppressor pathway that is broadly relevant in cancers and can be leveraged therapeutically.
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Affiliation(s)
- Gamal Ahmed Elfar
- NUS Department of Pathology, National University of Singapore, Yong Loo Lin School of Medicine, Singapore
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore
| | - Obed Aning
- NUS Department of Pathology, National University of Singapore, Yong Loo Lin School of Medicine, Singapore
| | - Tsz Wai Ngai
- NUS Department of Pathology, National University of Singapore, Yong Loo Lin School of Medicine, Singapore
| | - Pearlyn Yeo
- NUS Department of Pathology, National University of Singapore, Yong Loo Lin School of Medicine, Singapore
| | - Joel Wai Kit Chan
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore
| | - Shang Hong Sim
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore
| | - Leonard Goh
- NUS Department of Pathology, National University of Singapore, Yong Loo Lin School of Medicine, Singapore
| | - Ju Yuan
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore
| | - Cheryl Zi Jin Phua
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore
| | - Joanna Zhen Zhen Yeo
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore
- School of Biological Sciences, Nanyang Technological University, Singapore
| | - Shi Ya Mak
- Bioprocessing Technology Institute (BTI), Agency for Science, Technology and Research (A*STAR), Singapore
| | - Brian Kim Poh Goh
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore and National Cancer Centre Singapore, Singapore
| | - Pierce Kah-Hoe Chow
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore and National Cancer Centre Singapore, Singapore
- Surgery Academic ClinicalProgramme, Duke-NUS Medical School, National University of Singapore, Singapore
| | - Wai Leong Tam
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore
- School of Biological Sciences, Nanyang Technological University, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University Singapore, Singapore
| | - Ying Swan Ho
- Bioprocessing Technology Institute (BTI), Agency for Science, Technology and Research (A*STAR), Singapore
| | - Chit Fang Cheok
- NUS Department of Pathology, National University of Singapore, Yong Loo Lin School of Medicine, Singapore
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University Singapore, Singapore
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Gautam P, Ciuta I, Teif VB, Sinha SK. Predicting p53-dependent cell transitions from thermodynamic models. J Chem Phys 2024; 161:135101. [PMID: 39356070 DOI: 10.1063/5.0225166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Accepted: 09/18/2024] [Indexed: 10/03/2024] Open
Abstract
A cell's fate involves transitions among its various states, each defined by a distinct gene expression profile governed by the topology of gene regulatory networks, which are affected by 3D genome organization. Here, we develop thermodynamic models to determine the fate of a malignant cell as governed by the tumor suppressor p53 signaling network, taking into account long-range chromatin interactions in the mean-field approximation. The tumor suppressor p53 responds to stress by selectively triggering one of the potential transcription programs that influence many layers of cell signaling. These range from p53 phosphorylation to modulation of its DNA binding affinity, phase separation phenomena, and internal connectivity among cell fate genes. We use the minimum free energy of the system as a fundamental property of biological networks that influences the connection between the gene network topology and the state of the cell. We constructed models based on network topology and equilibrium thermodynamics. Our modeling shows that the binding of phosphorylated p53 to promoters of target genes can have properties of a first order phase transition. We apply our model to cancer cell lines ranging from breast cancer (MCF-7), colon cancer (HCT116), and leukemia (K562), with each one characterized by a specific network topology that determines the cell fate. Our results clarify the biological relevance of these mechanisms and suggest that they represent flexible network designs for switching between developmental decisions.
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Affiliation(s)
- Pankaj Gautam
- Theoretical and Computational Biophysical Chemistry Group, Department of Chemistry, Indian Institute of Technology Ropar, Rupnagar, Punjab 140001, India
| | - Isabella Ciuta
- School of Life Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, United Kingdom
| | - Vladimir B Teif
- School of Life Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, United Kingdom
| | - Sudipta Kumar Sinha
- Theoretical and Computational Biophysical Chemistry Group, Department of Chemistry, Indian Institute of Technology Ropar, Rupnagar, Punjab 140001, India
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Guo Y, Wu H, Wiesmüller L, Chen M. Canonical and non-canonical functions of p53 isoforms: potentiating the complexity of tumor development and therapy resistance. Cell Death Dis 2024; 15:412. [PMID: 38866752 PMCID: PMC11169513 DOI: 10.1038/s41419-024-06783-7] [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] [Revised: 05/26/2024] [Accepted: 05/28/2024] [Indexed: 06/14/2024]
Abstract
Full-length p53 (p53α) plays a pivotal role in maintaining genomic integrity and preventing tumor development. Over the years, p53 was found to exist in various isoforms, which are generated through alternative splicing, alternative initiation of translation, and internal ribosome entry site. p53 isoforms, either C-terminally altered or N-terminally truncated, exhibit distinct biological roles compared to p53α, and have significant implications for tumor development and therapy resistance. Due to a lack of part and/or complete C- or N-terminal domains, ectopic expression of some p53 isoforms failed to induce expression of canonical transcriptional targets of p53α like CDKN1A or MDM2, even though they may bind their promoters. Yet, p53 isoforms like Δ40p53α still activate subsets of targets including MDM2 and BAX. Furthermore, certain p53 isoforms transactivate even novel targets compared to p53α. More recently, non-canonical functions of p53α in DNA repair and of different isoforms in DNA replication unrelated to transcriptional activities were discovered, amplifying the potential of p53 as a master regulator of physiological and tumor suppressor functions in human cells. Both regarding canonical and non-canonical functions, alternative p53 isoforms frequently exert dominant negative effects on p53α and its partners, which is modified by the relative isoform levels. Underlying mechanisms include hetero-oligomerization, changes in subcellular localization, and aggregation. These processes ultimately influence the net activities of p53α and give rise to diverse cellular outcomes. Biological roles of p53 isoforms have implications for tumor development and cancer therapy resistance. Dysregulated expression of isoforms has been observed in various cancer types and is associated with different clinical outcomes. In conclusion, p53 isoforms have expanded our understanding of the complex regulatory network involving p53 in tumors. Unraveling the mechanisms underlying the biological roles of p53 isoforms provides new avenues for studies aiming at a better understanding of tumor development and developing therapeutic interventions to overcome resistance.
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Affiliation(s)
- Yitian Guo
- Department of Urology, Zhongda Hospital Southeast University, Nanjing, China.
| | - Hang Wu
- Department of Rehabilitation Medicine, Zhongda Hospital Southeast University, Nanjing, China
| | - Lisa Wiesmüller
- Department of Obstetrics and Gynecology, Ulm University, Ulm, Germany
| | - Ming Chen
- Department of Urology, Zhongda Hospital Southeast University, Nanjing, China.
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7
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Castaño BA, Schorer S, Guo Y, Calzetta NL, Gottifredi V, Wiesmüller L, Biber S. The levels of p53 govern the hierarchy of DNA damage tolerance pathway usage. Nucleic Acids Res 2024; 52:3740-3760. [PMID: 38321962 PMCID: PMC11039994 DOI: 10.1093/nar/gkae061] [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: 09/25/2023] [Revised: 01/12/2024] [Accepted: 02/01/2024] [Indexed: 02/08/2024] Open
Abstract
It is well-established that, through canonical functions in transcription and DNA repair, the tumor suppressor p53 plays a central role in safeguarding cells from the consequences of DNA damage. Recent data retrieved in tumor and stem cells demonstrated that p53 also carries out non-canonical functions when interacting with the translesion synthesis (TLS) polymerase iota (POLι) at DNA replication forks. This protein complex triggers a DNA damage tolerance (DDT) mechanism controlling the DNA replication rate. Given that the levels of p53 trigger non-binary rheostat-like functions in response to stress or during differentiation, we explore the relevance of the p53 levels for its DDT functions at the fork. We show that subtle changes in p53 levels modulate the contribution of some DDT factors including POLι, POLη, POLζ, REV1, PCNA, PRIMPOL, HLTF and ZRANB3 to the DNA replication rate. Our results suggest that the levels of p53 are central to coordinate the balance between DDT pathways including (i) fork-deceleration by the ZRANB3-mediated fork reversal factor, (ii) POLι-p53-mediated fork-slowing, (iii) POLι- and POLη-mediated TLS and (iv) PRIMPOL-mediated fork-acceleration. Collectively, our study reveals the relevance of p53 protein levels for the DDT pathway choice in replicating cells.
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Affiliation(s)
- Bryan A Castaño
- Department of Obstetrics and Gynecology, Ulm University, Ulm 89075, Germany
| | - Sabrina Schorer
- Department of Obstetrics and Gynecology, Ulm University, Ulm 89075, Germany
| | - Yitian Guo
- Department of Obstetrics and Gynecology, Ulm University, Ulm 89075, Germany
| | | | | | - Lisa Wiesmüller
- Department of Obstetrics and Gynecology, Ulm University, Ulm 89075, Germany
| | - Stephanie Biber
- Department of Obstetrics and Gynecology, Ulm University, Ulm 89075, Germany
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Wu Y, Bashir MA, Shao C, Wang H, Zhu J, Huang Q. Astaxanthin targets IL-6 and alleviates the LPS-induced adverse inflammatory response of macrophages. Food Funct 2024; 15:4207-4222. [PMID: 38512055 DOI: 10.1039/d4fo00610k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/22/2024]
Abstract
Numerous natural compounds are recognized for their anti-inflammatory properties attributed to antioxidant effects and the modulation of key inflammatory factors. Among them, astaxanthin (AST), a potent carotenoid antioxidant, remains relatively underexplored regarding its anti-inflammatory mechanisms and specific molecular targets. In this study, human monocytic leukemia cell-derived macrophages (THP-1) were selected as experimental cells, and lipopolysaccharides (LPS) served as inflammatory stimuli. Upon LPS treatment, the oxidative stress was significantly increased, accompanied by remarkable cellular damage. Moreover, LPSs escalated the expression of inflammation-related molecules. Our results demonstrate that AST intervention could effectively alleviate LPS-induced oxidative stress, facilitate cellular repair, and significantly attenuate inflammation. Further exploration of the anti-inflammatory mechanism revealed AST could substantially inhibit NF-κB translocation and activation, and mitigate inflammatory factor production by hindering NF-κB through the antioxidant mechanism. We further confirmed that AST exhibited protective effects against cell damage and reduced the injury from inflammatory cytokines by activating p53 and inhibiting STAT3. In addition, utilizing network pharmacology and in silico calculations based on molecular docking, molecular dynamics simulation, we identified interleukin-6 (IL-6) as a prominent core target of AST anti-inflammation, which was further validated by the RNA interference experiment. This IL-6 binding capacity actually enabled AST to curb the positive feedback loop of inflammatory factors, averting the onset of possible inflammatory storms. Therefore, this study offers a new possibility for the application and development of astaxanthin as a popular dietary supplement of anti-inflammatory or immunomodulatory function.
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Affiliation(s)
- Yahui Wu
- CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Anhui Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institute of Intelligent Agriculture, Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China.
- Science Island Branch of Graduate School, University of Science & Technology of China, Hefei 230026, China
| | - Mona A Bashir
- CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Anhui Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institute of Intelligent Agriculture, Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China.
- Science Island Branch of Graduate School, University of Science & Technology of China, Hefei 230026, China
| | - Changsheng Shao
- High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
| | - Han Wang
- CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Anhui Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institute of Intelligent Agriculture, Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China.
- Science Island Branch of Graduate School, University of Science & Technology of China, Hefei 230026, China
| | - Jianxia Zhu
- CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Anhui Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institute of Intelligent Agriculture, Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China.
- School of Nursing, Anhui Medical University, Hefei, Anhui 230032, China
| | - Qing Huang
- CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Anhui Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institute of Intelligent Agriculture, Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China.
- Science Island Branch of Graduate School, University of Science & Technology of China, Hefei 230026, China
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9
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Erazo-Oliveras A, Muñoz-Vega M, Salinas ML, Wang X, Chapkin RS. Dysregulation of cellular membrane homeostasis as a crucial modulator of cancer risk. FEBS J 2024; 291:1299-1352. [PMID: 36282100 PMCID: PMC10126207 DOI: 10.1111/febs.16665] [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: 06/18/2022] [Revised: 09/09/2022] [Accepted: 10/24/2022] [Indexed: 11/07/2022]
Abstract
Cellular membranes serve as an epicentre combining extracellular and cytosolic components with membranous effectors, which together support numerous fundamental cellular signalling pathways that mediate biological responses. To execute their functions, membrane proteins, lipids and carbohydrates arrange, in a highly coordinated manner, into well-defined assemblies displaying diverse biological and biophysical characteristics that modulate several signalling events. The loss of membrane homeostasis can trigger oncogenic signalling. More recently, it has been documented that select membrane active dietaries (MADs) can reshape biological membranes and subsequently decrease cancer risk. In this review, we emphasize the significance of membrane domain structure, organization and their signalling functionalities as well as how loss of membrane homeostasis can steer aberrant signalling. Moreover, we describe in detail the complexities associated with the examination of these membrane domains and their association with cancer. Finally, we summarize the current literature on MADs and their effects on cellular membranes, including various mechanisms of dietary chemoprevention/interception and the functional links between nutritional bioactives, membrane homeostasis and cancer biology.
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Affiliation(s)
- Alfredo Erazo-Oliveras
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Mónica Muñoz-Vega
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Michael L. Salinas
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Xiaoli Wang
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Robert S. Chapkin
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
- Center for Environmental Health Research; Texas A&M University; College Station, Texas, 77843; USA
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10
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Wei J, Dai J, Shi X, Zhao R, Fu G, Li R, Xia C, Zhang L, Zhou T, Wang H, Shi Y. Cadmium disrupts spermatogenic cell cycle via piRNA-DQ717867/p53 pathway. Reprod Toxicol 2024; 125:108554. [PMID: 38331007 DOI: 10.1016/j.reprotox.2024.108554] [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: 12/01/2023] [Revised: 01/17/2024] [Accepted: 01/30/2024] [Indexed: 02/10/2024]
Abstract
Cadmium (Cd) is a harmful environmental pollutant that disrupts public health, including respiratory, digestive, and reproductive systems. In this study, male rats were exposed to CdCl2 at a dose of 3 mg/kg by oral for 28 days to investigate the impact on spermatogenesis. Testis tissue samples were collected after sacrifice, and piRNA expression levels were measured using piRNA microarray and qPCR. PiRNAs, specialized molecules involved in spermatogenesis, were examined. CdCl2 exposure led to disrupted piRNA expression, particularly in piRNA-DQ759395 in rats. This piRNA was found to have a binding site with p53, and a similar piRNA-DQ717867 was discovered in mice. In GC-2spd cells, CdCl2 exposure increased piRNA-DQ717867 expression, which resulted in cell cycle arrest and abnormal expression of cell cycle-related proteins. The activation of p53-related pathways and disruptions in cell cycle regulation were also observed. Antagomir-717867 transfections and PFT-a pretreatment in GC-2spd cells supported the involvement of piRNA-DQ717867 in regulating cell cycle-related proteins. This study suggests that Cd exposure induces abnormal expression of piRNA-DQ759395 in rat testis and that piRNA-DQ717867 may regulate p53, causing cell cycle abnormalities in GC-2spd cells. These findings help understand the mechanisms of male reproductive toxicity caused by Cd exposure and emphasize the role of piRNAs in cell cycle regulation and male reproductive health.
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Affiliation(s)
- Jiaoyang Wei
- School of Public Health, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Wuhan University of Science and Technology, China
| | - Juan Dai
- Wuhan centers for Disease Prevention and Control, China
| | - Xiaofan Shi
- Qinghai centers for Disease Prevention and Control, China
| | - Ruixue Zhao
- School of Public Health, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Wuhan University of Science and Technology, China
| | | | - Rui Li
- Central China Normal University, China
| | - Chao Xia
- Ezhou centers for Disease Prevention and Control, China
| | - Ling Zhang
- School of Public Health, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Wuhan University of Science and Technology, China
| | - Ting Zhou
- School of Public Health, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Wuhan University of Science and Technology, China
| | - Huaiji Wang
- Wuhan centers for Disease Prevention and Control, China.
| | - Yuqin Shi
- School of Public Health, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Wuhan University of Science and Technology, China.
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11
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Serra F, Nieto-Aliseda A, Fanlo-Escudero L, Rovirosa L, Cabrera-Pasadas M, Lazarenkov A, Urmeneta B, Alcalde-Merino A, Nola EM, Okorokov AL, Fraser P, Graupera M, Castillo SD, Sardina JL, Valencia A, Javierre BM. p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response. Nat Commun 2024; 15:2821. [PMID: 38561401 PMCID: PMC10984980 DOI: 10.1038/s41467-024-46666-1] [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: 06/15/2023] [Accepted: 03/04/2024] [Indexed: 04/04/2024] Open
Abstract
Activation of the p53 tumor suppressor triggers a transcriptional program to control cellular response to stress. However, the molecular mechanisms by which p53 controls gene transcription are not completely understood. Here, we uncover the critical role of spatio-temporal genome architecture in this process. We demonstrate that p53 drives direct and indirect changes in genome compartments, topologically associating domains, and DNA loops prior to one hour of its activation, which escort the p53 transcriptional program. Focusing on p53-bound enhancers, we report 340 genes directly regulated by p53 over a median distance of 116 kb, with 74% of these genes not previously identified. Finally, we showcase that p53 controls transcription of distal genes through newly formed and pre-existing enhancer-promoter loops in a cohesin dependent manner. Collectively, our findings demonstrate a previously unappreciated architectural role of p53 as regulator at distinct topological layers and provide a reliable set of new p53 direct target genes that may help designs of cancer therapies.
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Affiliation(s)
- François Serra
- Josep Carreras Leukaemia Research Institute, Barcelona, Spain
| | | | | | | | - Mónica Cabrera-Pasadas
- Josep Carreras Leukaemia Research Institute, Barcelona, Spain
- Barcelona Supercomputing Center, Barcelona, Spain
| | | | - Blanca Urmeneta
- Josep Carreras Leukaemia Research Institute, Barcelona, Spain
| | | | - Emanuele M Nola
- Josep Carreras Leukaemia Research Institute, Barcelona, Spain
| | - Andrei L Okorokov
- Wolfson Institute for Biomedical Research, University College London, London, UK
| | - Peter Fraser
- Department of Biological Science, Florida State University, Tallahassee, FL, USA
| | - Mariona Graupera
- Josep Carreras Leukaemia Research Institute, Barcelona, Spain
- Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
- CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | | | - Jose L Sardina
- Josep Carreras Leukaemia Research Institute, Barcelona, Spain
| | - Alfonso Valencia
- Barcelona Supercomputing Center, Barcelona, Spain
- Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
| | - Biola M Javierre
- Josep Carreras Leukaemia Research Institute, Barcelona, Spain.
- Institute for Health Science Research Germans Trias i Pujol, Barcelona, Spain.
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12
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Cinciripini PM, Wetter DW, Wang J, Yu R, Kypriotakis G, Kumar T, Robinson JD, Cui Y, Green CE, Bergen AW, Kosten TR, Scherer SE, Shete S. Deep sequencing of candidate genes identified 14 variants associated with smoking abstinence in an ethnically diverse sample. Sci Rep 2024; 14:6385. [PMID: 38493193 PMCID: PMC10944542 DOI: 10.1038/s41598-024-56750-7] [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: 07/18/2023] [Accepted: 03/11/2024] [Indexed: 03/18/2024] Open
Abstract
Despite the large public health toll of smoking, genetic studies of smoking cessation have been limited with few discoveries of risk or protective loci. We investigated common and rare variant associations with success in quitting smoking using a cohort from 8 randomized controlled trials involving 2231 participants and a total of 10,020 common and 24,147 rare variants. We identified 14 novel markers including 6 mapping to genes previously related to psychiatric and substance use disorders, 4 of which were protective (CYP2B6 (rs1175607105), HTR3B (rs1413172952; rs1204720503), rs80210037 on chr15), and 2 of which were associated with reduced cessation (PARP15 (rs2173763), SCL18A2 (rs363222)). The others mapped to areas associated with cancer including FOXP1 (rs1288980) and ZEB1 (rs7349). Network analysis identified significant canonical pathways for the serotonin receptor signaling pathway, nicotine and bupropion metabolism, and several related to tumor suppression. Two novel markers (rs6749438; rs6718083) on chr2 are flanked by genes associated with regulation of bodyweight. The identification of novel loci in this study can provide new targets of pharmacotherapy and inform efforts to develop personalized treatments based on genetic profiles.
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Affiliation(s)
- Paul M Cinciripini
- Department of Behavioral Science, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
| | - David W Wetter
- Department of Department of Population Health Sciences, University of Utah and Huntsman Cancer Institute, Salt Lake City, Utah, 84112, USA
| | - Jian Wang
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Robert Yu
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - George Kypriotakis
- Department of Behavioral Science, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
| | - Tapsi Kumar
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Jason D Robinson
- Department of Behavioral Science, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Yong Cui
- Department of Behavioral Science, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Charles E Green
- Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX, 77030, USA
| | | | - Thomas R Kosten
- Department of Psychiatry, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Steven E Scherer
- Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Sanjay Shete
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
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13
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Indeglia A, Murphy ME. Elucidating the chain of command: our current understanding of critical target genes for p53-mediated tumor suppression. Crit Rev Biochem Mol Biol 2024; 59:128-138. [PMID: 38661126 PMCID: PMC11209770 DOI: 10.1080/10409238.2024.2344465] [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: 01/31/2024] [Revised: 03/13/2024] [Accepted: 04/15/2024] [Indexed: 04/26/2024]
Abstract
TP53 encodes a transcription factor that is centrally-involved in several pathways, including the control of metabolism, the stress response, DNA repair, cell cycle arrest, senescence, programmed cell death, and others. Since the discovery of TP53 as the most frequently-mutated tumor suppressor gene in cancer over four decades ago, the field has focused on uncovering target genes of this transcription factor that are essential for tumor suppression. This search has been fraught with red herrings, however. Dozens of p53 target genes were discovered that had logical roles in tumor suppression, but subsequent data showed that most were not tumor suppressive, and were dispensable for p53-mediated tumor suppression. In this review, we focus on p53 transcriptional targets in two categories: (1) canonical targets like CDKN1A (p21) and BBC3 (PUMA), which clearly play critical roles in p53-mediated cell cycle arrest/senescence and cell death, but which are not mutated in cancer, and for which knockout mice fail to develop spontaneous tumors; and (2) a smaller category of recently-described p53 target genes that are mutated in human cancer, and which appear to be critical for tumor suppression by p53. Interestingly, many of these genes encode proteins that control broad cellular pathways, like splicing and protein degradation, and several of them encode proteins that feed back to regulate p53. These include ZMAT3, GLS2, PADI4, ZBXW7, RFX7, and BTG2. The findings from these studies provide a more complex, but exciting, potential framework for understanding the role of p53 in tumor suppression.
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Affiliation(s)
- Alexandra Indeglia
- The Wistar Institute, Philadelphia PA 19104
- Biochemistry and Molecular Biophysics Graduate Group, The University of Pennsylvania Perelman School of Medicine, Philadelphia PA 19104
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14
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Ling ZN, Jiang YF, Ru JN, Lu JH, Ding B, Wu J. Amino acid metabolism in health and disease. Signal Transduct Target Ther 2023; 8:345. [PMID: 37699892 PMCID: PMC10497558 DOI: 10.1038/s41392-023-01569-3] [Citation(s) in RCA: 156] [Impact Index Per Article: 78.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 06/12/2023] [Accepted: 07/13/2023] [Indexed: 09/14/2023] Open
Abstract
Amino acids are the building blocks of protein synthesis. They are structural elements and energy sources of cells necessary for normal cell growth, differentiation and function. Amino acid metabolism disorders have been linked with a number of pathological conditions, including metabolic diseases, cardiovascular diseases, immune diseases, and cancer. In the case of tumors, alterations in amino acid metabolism can be used not only as clinical indicators of cancer progression but also as therapeutic strategies. Since the growth and development of tumors depend on the intake of foreign amino acids, more and more studies have targeted the metabolism of tumor-related amino acids to selectively kill tumor cells. Furthermore, immune-related studies have confirmed that amino acid metabolism regulates the function of effector T cells and regulatory T cells, affecting the function of immune cells. Therefore, studying amino acid metabolism associated with disease and identifying targets in amino acid metabolic pathways may be helpful for disease treatment. This article mainly focuses on the research of amino acid metabolism in tumor-oriented diseases, and reviews the research and clinical research progress of metabolic diseases, cardiovascular diseases and immune-related diseases related to amino acid metabolism, in order to provide theoretical basis for targeted therapy of amino acid metabolism.
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Affiliation(s)
- Zhe-Nan Ling
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, Zhejiang Province, 310003, P.R. China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Zhejiang Province, P.R. China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang Province, P.R. China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang Province, P.R. China
| | - Yi-Fan Jiang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, Zhejiang Province, 310003, P.R. China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Zhejiang Province, P.R. China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang Province, P.R. China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang Province, P.R. China
| | - Jun-Nan Ru
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, Zhejiang Province, 310003, P.R. China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Zhejiang Province, P.R. China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang Province, P.R. China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang Province, P.R. China
| | - Jia-Hua Lu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, Zhejiang Province, 310003, P.R. China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Zhejiang Province, P.R. China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang Province, P.R. China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang Province, P.R. China
| | - Bo Ding
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, Zhejiang Province, 310003, P.R. China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Zhejiang Province, P.R. China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang Province, P.R. China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang Province, P.R. China
| | - Jian Wu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, Zhejiang Province, 310003, P.R. China.
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Zhejiang Province, P.R. China.
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang Province, P.R. China.
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang Province, P.R. China.
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15
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Choudhary HB, Mandlik SK, Mandlik DS. Role of p53 suppression in the pathogenesis of hepatocellular carcinoma. World J Gastrointest Pathophysiol 2023; 14:46-70. [PMID: 37304923 PMCID: PMC10251250 DOI: 10.4291/wjgp.v14.i3.46] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/19/2023] [Accepted: 05/31/2023] [Indexed: 06/01/2023] Open
Abstract
In the world, hepatocellular carcinoma (HCC) is among the top 10 most prevalent malignancies. HCC formation has indeed been linked to numerous etiological factors, including alcohol usage, hepatitis viruses and liver cirrhosis. Among the most prevalent defects in a wide range of tumours, notably HCC, is the silencing of the p53 tumour suppressor gene. The control of the cell cycle and the preservation of gene function are both critically important functions of p53. In order to pinpoint the core mechanisms of HCC and find more efficient treatments, molecular research employing HCC tissues has been the main focus. Stimulated p53 triggers necessary reactions that achieve cell cycle arrest, genetic stability, DNA repair and the elimination of DNA-damaged cells’ responses to biological stressors (like oncogenes or DNA damage). To the contrary hand, the oncogene protein of the murine double minute 2 (MDM2) is a significant biological inhibitor of p53. MDM2 causes p53 protein degradation, which in turn adversely controls p53 function. Despite carrying wt-p53, the majority of HCCs show abnormalities in the p53-expressed apoptotic pathway. High p53 in-vivo expression might have two clinical impacts on HCC: (1) Increased levels of exogenous p53 protein cause tumour cells to undergo apoptosis by preventing cell growth through a number of biological pathways; and (2) Exogenous p53 makes HCC susceptible to various anticancer drugs. This review describes the functions and primary mechanisms of p53 in pathological mechanism, chemoresistance and therapeutic mechanisms of HCC.
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Affiliation(s)
- Heena B Choudhary
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Satish K Mandlik
- Department of Pharmaceutics, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Deepa S Mandlik
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
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16
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Sun SY, Crago A. MDM2 Implications for Potential Molecular Pathogenic Therapies of Soft-Tissue Tumors. J Clin Med 2023; 12:3638. [PMID: 37297833 PMCID: PMC10253559 DOI: 10.3390/jcm12113638] [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: 03/26/2023] [Revised: 04/14/2023] [Accepted: 05/03/2023] [Indexed: 06/12/2023] Open
Abstract
Murine double minute 2 (MDM2, gene name MDM2) is an oncogene that mainly codes for a protein that acts as an E3 ubiquitin ligase, which targets the tumor suppressor protein p53 for degradation. Overexpression of MDM2 regulates the p53 protein levels by binding to it and promoting its degradation by the 26S proteasome. This leads to the inhibition of p53's ability to regulate cell cycle progression and apoptosis, allowing for uncontrolled cell growth, and can contribute to the development of soft-tissue tumors. The application of cellular stress leads to changes in the binding of MDM2 to p53, which prevents MDM2 from degrading p53. This results in an increase in p53 levels, which triggers either cell cycle arrest or apoptosis. Inhibiting the function of MDM2 has been identified as a potential therapeutic strategy for treating these types of tumors. By blocking the activity of MDM2, p53 function can be restored, potentially leading to tumor cell death and inhibiting the growth of tumors. However, further research is needed to fully understand the implications of MDM2 inhibition for the treatment of soft-tissue tumors and to determine the safety and efficacy of these therapies in clinical trials. An overview of key milestones and potential uses of MDM2 research is presented in this review.
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Affiliation(s)
- Sylvia Yao Sun
- Sarcoma Biology Laboratory, Department of Surgery, Memorial Sloan Kettering Cancer Center, 417 E 618 St, New York, NY 10065, USA
| | - Aimee Crago
- Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
- Department of Surgery, Weill Cornell Medical Center, 525 E 68th St M 404, New York, NY 10065, USA
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17
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Łasut-Szyszka B, Rusin M. The Wheel of p53 Helps to Drive the Immune System. Int J Mol Sci 2023; 24:ijms24087645. [PMID: 37108808 PMCID: PMC10143509 DOI: 10.3390/ijms24087645] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/18/2023] [Accepted: 04/18/2023] [Indexed: 04/29/2023] Open
Abstract
The p53 tumor suppressor protein is best known as an inhibitor of the cell cycle and an inducer of apoptosis. Unexpectedly, these functions of p53 are not required for its tumor suppressive activity in animal models. High-throughput transcriptomic investigations as well as individual studies have demonstrated that p53 stimulates expression of many genes involved in immunity. Probably to interfere with its immunostimulatory role, many viruses code for proteins that inactivate p53. Judging by the activities of immunity-related p53-regulated genes it can be concluded that p53 is involved in detection of danger signals, inflammasome formation and activation, antigen presentation, activation of natural killer cells and other effectors of immunity, stimulation of interferon production, direct inhibition of virus replication, secretion of extracellular signaling molecules, production of antibacterial proteins, negative feedback loops in immunity-related signaling pathways, and immunologic tolerance. Many of these p53 functions have barely been studied and require further, more detailed investigations. Some of them appear to be cell-type specific. The results of transcriptomic studies have generated many new hypotheses on the mechanisms utilized by p53 to impact on the immune system. In the future, these mechanisms may be harnessed to fight cancer and infectious diseases.
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Affiliation(s)
- Barbara Łasut-Szyszka
- Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-101 Gliwice, Poland
| | - Marek Rusin
- Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-101 Gliwice, Poland
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18
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Ghosh A, Ganguly D. Structural modulation of p53TAD1-TAZ2 complex upon mutations and post-translational modification. J Biomol Struct Dyn 2023; 41:176-185. [PMID: 34787057 DOI: 10.1080/07391102.2021.2004235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The tumour suppressing p53 is a target for genetic alterations in human cancer. Native p53, found in latent state in cells, gets activated following various intracellular or extracellular responses. It plays imperative role in cell-cycle control, via growth-arrest, DNA repair and apoptosis, mainly regulated by post-translational modifications (PTM). However, the influence of PTMs on the activity of p53 is still under extensive experimental and computational study. There are numerous PTM sites in p53, which are reported to regulate its binding affinities with other proteins. Of the many, Thr18 at transactivational domain (TAD) of p53 is reported to amplify p53 activity upon phosphorylation. To understand the molecular basis of p53 recognition by its binding partner upon mutations and PTMs, we have exploited all atom molecular dynamic (MD) simulation of p53TAD1 bound to TAZ2 domain of p300. The MD simulation inferred that phosphorylated and mutated Thr18, as a phospho-mimic, bound with TAZ2, redistributed the charge environment of the interface, thereby modulating the stronger interactions with TAZ2 to enhance the binding efficiency. The electrostatic interactions due to different charge environment together with H-bonding and hydrophobic interaction dictate diverse binding approach between the two. The results of this computational study further explain the importance of the Thr18 as a PTM site in atomistic detail, hence shedding further light to the understanding of how PTMs are imperative for p53 activity to protect the cellular world.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Anamika Ghosh
- Department of Chemistry, Indian Institute of Engineering Science and Technology, Howrah, India
| | - Debabani Ganguly
- Centre for Health Science and Technology, JIS Institute of Advanced Studies and Research Kolkata, JIS University, Kolkata, India
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19
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Patil MR, Bihari A. A comprehensive study of p53 protein. J Cell Biochem 2022; 123:1891-1937. [PMID: 36183376 DOI: 10.1002/jcb.30331] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 09/02/2022] [Accepted: 09/13/2022] [Indexed: 01/10/2023]
Abstract
The protein p53 has been extensively investigated since it was found 43 years ago and has become a "guardian of the genome" that regulates the division of cells by preventing the growth of cells and dividing them, that is, inhibits the development of tumors. Initial proof of protein existence by researchers in the mid-1970s was found by altering and regulating the SV40 big T antigen termed the A protein. Researchers demonstrated how viruses play a role in cancer by employing viruses' ability to create T-antigens complex with viral tumors, which was discovered in 1979 following a viral analysis and cancer analog research. Researchers later in the year 1989 explained that in Murine Friend, a virus-caused erythroleukemia, commonly found that p53 was inactivated to suggest that p53 could be a "tumor suppressor gene." The TP53 gene, encoding p53, is one of human cancer's most frequently altered genes. The protein-regulated biological functions of all p53s include cell cycles, apoptosis, senescence, metabolism of the DNA, angiogenesis, cell differentiation, and immunological response. We tried to unfold the history of the p53 protein, which was discovered long back in 1979, that is, 43 years of research on p53, and how p53's function has been developed through time in this article.
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Affiliation(s)
- Manisha R Patil
- Department of Computer-Applications, School of Information Technology and Engineering, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Anand Bihari
- Department of Computational Intelligence, School of Computer Science and Engineering, Vellore Institute of Technology, Vellore, Tamil Nadu, India
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20
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Werner H, LeRoith D. Hallmarks of cancer: The insulin-like growth factors perspective. Front Oncol 2022; 12:1055589. [PMID: 36479090 PMCID: PMC9720135 DOI: 10.3389/fonc.2022.1055589] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 11/07/2022] [Indexed: 08/30/2023] Open
Abstract
The identification of a series of attributes or hallmarks that are shared by virtually all cancer cells constitutes a true milestone in cancer research. The conceptualization of a catalogue of common genetic, molecular, biochemical and cellular events under a unifying Hallmarks of Cancer idea had a major impact in oncology. Furthermore, the fact that different types of cancer, ranging from pediatric tumors and leukemias to adult epithelial cancers, share a large number of fundamental traits reflects the universal nature of the biological events involved in oncogenesis. The dissection of a complex disease like cancer into a finite directory of hallmarks is of major basic and translational relevance. The role of insulin-like growth factor-1 (IGF1) as a progression/survival factor required for normal cell cycle transition has been firmly established. Similarly well characterized are the biochemical and cellular activities of IGF1 and IGF2 in the chain of events leading from a phenotypically normal cell to a diseased one harboring neoplastic traits, including growth factor independence, loss of cell-cell contact inhibition, chromosomal abnormalities, accumulation of mutations, activation of oncogenes, etc. The purpose of the present review is to provide an in-depth evaluation of the biology of IGF1 at the light of paradigms that emerge from analysis of cancer hallmarks. Given the fact that the IGF1 axis emerged in recent years as a promising therapeutic target, we believe that a careful exploration of this signaling system might be of critical importance on our ability to design and optimize cancer therapies.
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Affiliation(s)
- Haim Werner
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Derek LeRoith
- Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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21
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Borsos BN, Pantazi V, Páhi ZG, Majoros H, Ujfaludi Z, Berzsenyi I, Pankotai T. The role of p53 in the DNA damage-related ubiquitylation of S2P RNAPII. PLoS One 2022; 17:e0267615. [PMID: 35511765 PMCID: PMC9070946 DOI: 10.1371/journal.pone.0267615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 04/11/2022] [Indexed: 11/19/2022] Open
Abstract
DNA double-strand breaks are one of the most deleterious lesions for the cells, therefore understanding the macromolecular interactions of the DNA repair-related mechanisms is essential. DNA damage triggers transcription silencing at the damage site, leading to the removal of the elongating RNA polymerase II (S2P RNAPII) from this locus, which provides accessibility for the repair factors to the lesion. We previously demonstrated that following transcription block, p53 plays a pivotal role in transcription elongation by interacting with S2P RNAPII. In the current study, we reveal that p53 is involved in the fine-tune regulation of S2P RNAPII ubiquitylation. Furthermore, we emphasize the potential role of p53 in delaying the premature ubiquitylation and the subsequent chromatin removal of S2P RNAPII as a response to transcription block.
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Affiliation(s)
- Barbara N. Borsos
- Institute of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Vasiliki Pantazi
- Institute of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Zoltán G. Páhi
- Institute of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Hajnalka Majoros
- Institute of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Zsuzsanna Ujfaludi
- Institute of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Ivett Berzsenyi
- Institute of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Tibor Pankotai
- Institute of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
- * E-mail:
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22
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Guo C, Guo L, Peng C, Jia Y, Yang Y, Wang X, Zeng M, Wang D, Liu C, Zhao M, Chen J, Tang Z. p53-driven replication stress in nucleoli of malignant epithelial ovarian cancer. Exp Cell Res 2022; 417:113225. [DOI: 10.1016/j.yexcr.2022.113225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 04/14/2022] [Accepted: 05/22/2022] [Indexed: 11/30/2022]
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23
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Exploring the composition of Syringa reticulata subsp. amurensis seed and its underlying mechanism against chronic bronchitis. CHINESE JOURNAL OF ANALYTICAL CHEMISTRY 2022. [DOI: 10.1016/j.cjac.2022.100132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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24
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Up-regulation of ST18 in pemphigus vulgaris drives a self-amplifying p53-dependent pathomechanism resulting in decreased desmoglein 3 expression. Sci Rep 2022; 12:5958. [PMID: 35396567 PMCID: PMC8993920 DOI: 10.1038/s41598-022-09951-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 03/14/2022] [Indexed: 11/14/2022] Open
Abstract
Pemphigus vulgaris (PV) is a life-threatening autoimmune mucocutaneous blistering disease which is to a large extent genetically determined, and results, at least in part, from the deleterious activity of autoantibodies directed against desmoglein (DSG)3, a prominent intra-epidermal adhesion molecule. Those autoantibodies lead to decreased membranal DSG3 expression in keratinocytes (KCs), thereby destabilizing cell–cell adhesion within the epidermis and leading to blister formation. We previously showed that rs17315309, a strong risk variant for PV within the promoter of the ST18 transcription factor gene, promotes epidermal ST18 up-regulation in a p53/p63-dependent manner. Accordingly, ST18 was found to be overexpressed in the skin of PV patients. Increased ST18 expression was then shown to markedly augment PV autoantibodies-mediated loss of KCs cohesion. Here, we demonstrate that ST18 overexpression significantly increases autoantibody-mediated DSG3 down-regulation in keratinocytes. In addition, DSG3 decreased expression boosts p53 function through p38 mitogen-activated protein kinase (p38MAPK) activation and dramatically augments p53-dependent ST18 promoter activity. Finally, the PV risk variant rs17315309 is associated with increased p53 expression in PV skin. Taken collectively, these observations reveal a novel self-amplifying pathomechanism involving ST18, DSG3, p38 and p53, capable of perpetuating disease activity, and therefore indicative of novel actionable molecular targets in PV.
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25
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Engeland K. Cell cycle regulation: p53-p21-RB signaling. Cell Death Differ 2022; 29:946-960. [PMID: 35361964 PMCID: PMC9090780 DOI: 10.1038/s41418-022-00988-z] [Citation(s) in RCA: 570] [Impact Index Per Article: 190.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 03/14/2022] [Accepted: 03/15/2022] [Indexed: 12/12/2022] Open
Abstract
The retinoblastoma protein RB and the transcription factor p53 are central tumor suppressors. They are often found inactivated in various tumor types. Both proteins play central roles in regulating the cell division cycle. RB forms complexes with the E2F family of transcription factors and downregulates numerous genes. Among the RB-E2F target genes, a large number code for key cell cycle regulators. Their transcriptional repression by the RB-E2F complex is released through phosphorylation of RB, leading to expression of the cell cycle regulators. The release from repression can be prevented by the cyclin-dependent kinase inhibitor p21/CDKN1A. The CDKN1A gene is transcriptionally activated by p53. Taken together, these elements constitute the p53-p21-RB signaling pathway. Following activation of p53, for example by viral infection or induction of DNA damage, p21 expression is upregulated. High levels of p21 then result in RB-E2F complex formation and downregulation of a large number of cell cycle genes. Thus, p53-dependent transcriptional repression is indirect. The reduced expression of the many regulators leads to cell cycle arrest. Examination of the p53-p21-RB targets and genes controlled by the related p53-p21-DREAM signaling pathway reveals that there is a large overlap of the two groups. Mechanistically this can be explained by replacing RB-E2F complexes with the DREAM transcriptional repressor complex at E2F sites in target promoters. In contrast to RB-E2F, DREAM can downregulate genes also through CHR transcription factor binding sites. This results in a distinct gene set controlled by p53-p21-DREAM signaling independent of RB-E2F. Furthermore, RB has non-canonical functions without binding to E2F and DNA. Such a role of RB supporting DREAM formation may be exerted by the RB-SKP2-p27-cyclin A/E-CDK2-p130-DREAM link. In the current synopsis, the mechanism of regulation by p53-p21-RB signaling is assessed and the overlap with p53-p21-DREAM signaling is examined. ![]()
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Affiliation(s)
- Kurt Engeland
- Molecular Oncology, Medical School, University of Leipzig, Semmelweisstrasse 14, 04103, Leipzig, Germany.
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26
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Engineered circular ADAR-recruiting RNAs increase the efficiency and fidelity of RNA editing in vitro and in vivo. Nat Biotechnol 2022; 40:946-955. [PMID: 35145313 DOI: 10.1038/s41587-021-01180-3] [Citation(s) in RCA: 95] [Impact Index Per Article: 31.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 12/01/2021] [Indexed: 12/14/2022]
Abstract
Current methods for programmed RNA editing using endogenous ADAR enzymes and engineered ADAR-recruiting RNAs (arRNAs) suffer from low efficiency and bystander off-target editing. Here, we describe LEAPER 2.0, an updated version of LEAPER that uses covalently closed circular arRNAs, termed circ-arRNAs. We demonstrate on average ~3.1-fold higher editing efficiency than their linear counterparts when expressed in cells or delivered as in vitro-transcribed circular RNA oligonucleotides. To lower off-target editing we deleted pairings of uridines with off-target adenosines, which almost completely eliminated bystander off-target adenosine editing. Engineered circ-arRNAs enhanced the efficiency and fidelity of editing endogenous CTNNB1 and mutant TP53 transcripts in cell culture. Delivery of circ-arRNAs using adeno-associated virus in a mouse model of Hurler syndrome corrected the pathogenic point mutation and restored α-L-iduronidase catalytic activity, lowering glycosaminoglycan accumulation in the liver. LEAPER 2.0 provides a new design of arRNA that enables more precise, efficient RNA editing with broad applicability for therapy and basic research.
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27
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Marques MA, de Andrade GC, Silva JL, de Oliveira GAP. Protein of a thousand faces: The tumor-suppressive and oncogenic responses of p53. Front Mol Biosci 2022; 9:944955. [PMID: 36090037 PMCID: PMC9452956 DOI: 10.3389/fmolb.2022.944955] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 07/18/2022] [Indexed: 12/30/2022] Open
Abstract
The p53 protein is a pleiotropic regulator working as a tumor suppressor and as an oncogene. Depending on the cellular insult and the mutational status, p53 may trigger opposing activities such as cell death or survival, senescence and cell cycle arrest or proliferative signals, antioxidant or prooxidant activation, glycolysis, or oxidative phosphorylation, among others. By augmenting or repressing specific target genes or directly interacting with cellular partners, p53 accomplishes a particular set of activities. The mechanism in which p53 is activated depends on increased stability through post-translational modifications (PTMs) and the formation of higher-order structures (HOS). The intricate cell death and metabolic p53 response are reviewed in light of gaining stability via PTM and HOS formation in health and disease.
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Affiliation(s)
- Mayra A. Marques
- *Correspondence: Mayra A. Marques, ; Guilherme A. P. de Oliveira,
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28
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Chamberlain V, Drew Y, Lunec J. Tipping Growth Inhibition into Apoptosis by Combining Treatment with MDM2 and WIP1 Inhibitors in p53 WT Uterine Leiomyosarcoma. Cancers (Basel) 2021; 14:cancers14010014. [PMID: 35008180 PMCID: PMC8750798 DOI: 10.3390/cancers14010014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 12/08/2021] [Accepted: 12/16/2021] [Indexed: 12/24/2022] Open
Abstract
As there is no optimal therapeutic strategy defined for women with advanced or recurrent uLMS, there is an urgent need for the discovery of novel, targeted approaches. One such area of interest is the pharmacological inhibition of the MDM2-p53 interaction with small-molecular-weight MDM2 inhibitors. Growth inhibition and cytotoxic assays were used to evaluate uLMS cell line responses to MDM2 inhibitors as single agents and in combination, qRT-PCR to assess transcriptional changes and Caspase-Glo 3/7 assay to detect apoptosis. RG7388 and HDM201 are potent, selective antagonists of the MDM2-p53 interaction that can effectively stabilise and activate p53 in a dose-dependent manner. GSK2830371, a potent and selective WIP1 phosphatase inhibitor, was shown to significantly potentiate the growth inhibitory effects of RG7388 and HDM201, and significantly increase the mRNA expression of p53 transcriptional target genes in a p53WT cell line at a concentration that has no growth inhibitory effects as a single agent. RG7388, HDM201 and GSK2830371 failed to induce apoptosis as single agents; however, a combination treatment tipped cells into apoptosis from senescence. These data present the possibility of MDM2 and WIP1 inhibitor combinations as a potential treatment option for p53WT uLMS patients that warrants further investigation.
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Affiliation(s)
- Victoria Chamberlain
- Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; (V.C.); (Y.D.)
| | - Yvette Drew
- Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; (V.C.); (Y.D.)
- BC Cancer Centre Vancouver and Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 4EH, Canada
| | - John Lunec
- Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; (V.C.); (Y.D.)
- Correspondence:
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29
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Tang L, Xiao Q, Mei Y, He S, Zhang Z, Wang R, Wang W. Insights on functionalized carbon nanotubes for cancer theranostics. J Nanobiotechnology 2021; 19:423. [PMID: 34915901 PMCID: PMC8679967 DOI: 10.1186/s12951-021-01174-y] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 12/01/2021] [Indexed: 12/13/2022] Open
Abstract
Despite the exciting breakthroughs in medical technology, cancer still accounts for one of the principle triggers of death and conventional therapeutic modalities often fail to attain an effective cure. Recently, nanobiotechnology has made huge advancement in cancer therapy with gigantic application potential because of their ability in achieving precise and controlled drug release, elevating drug solubility and reducing adverse effects. Carbon nanotubes (CNTs), one of the most promising carbon-related nanomaterials, have already achieved much success in biomedical field. Due to their excellent optical property, thermal and electronic conductivity, easy functionalization ability and high drug loading capacity, CNTs can be applied in a multifunctional way for cancer treatment and diagnosis. In this review, we will give an overview of the recent progress of CNT-based drug delivery systems in cancer theranostics, which emphasizes their targetability to intracellular components of tumor cells and extracellular elements in tumor microenvironment. Moreover, a detailed introduction on how CNTs penetrate inside the tumor cells to reach their sites of action and achieve the therapeutic effects, as well as their diagnostic applications will be highlighted. ![]()
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Affiliation(s)
- Lu Tang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.,NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing, 210009, People's Republic of China
| | - Qiaqia Xiao
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.,NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing, 210009, People's Republic of China
| | - Yijun Mei
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.,NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing, 210009, People's Republic of China
| | - Shun He
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.,NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing, 210009, People's Republic of China
| | - Ziyao Zhang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.,NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing, 210009, People's Republic of China
| | - Ruotong Wang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.,NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing, 210009, People's Republic of China
| | - Wei Wang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China. .,NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.
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30
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Mehta S, Campbell H, Drummond CJ, Li K, Murray K, Slatter T, Bourdon JC, Braithwaite AW. Adaptive homeostasis and the p53 isoform network. EMBO Rep 2021; 22:e53085. [PMID: 34779563 PMCID: PMC8647153 DOI: 10.15252/embr.202153085] [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: 04/18/2021] [Revised: 10/12/2021] [Accepted: 10/28/2021] [Indexed: 12/25/2022] Open
Abstract
All living organisms have developed processes to sense and address environmental changes to maintain a stable internal state (homeostasis). When activated, the p53 tumour suppressor maintains cell and organ integrity and functions in response to homeostasis disruptors (stresses) such as infection, metabolic alterations and cellular damage. Thus, p53 plays a fundamental physiological role in maintaining organismal homeostasis. The TP53 gene encodes a network of proteins (p53 isoforms) with similar and distinct biochemical functions. The p53 network carries out multiple biological activities enabling cooperation between individual cells required for long‐term survival of multicellular organisms (animals) in response to an ever‐changing environment caused by mutation, infection, metabolic alteration or damage. In this review, we suggest that the p53 network has evolved as an adaptive response to pathogen infections and other environmental selection pressures.
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Affiliation(s)
- Sunali Mehta
- Department of Pathology, School of Medicine, University of Otago, Dunedin, New Zealand.,Maurice Wilkins Centre for Biodiscovery, University of Otago, Dunedin, New Zealand
| | - Hamish Campbell
- Department of Pathology, School of Medicine, University of Otago, Dunedin, New Zealand
| | - Catherine J Drummond
- Department of Pathology, School of Medicine, University of Otago, Dunedin, New Zealand.,Maurice Wilkins Centre for Biodiscovery, University of Otago, Dunedin, New Zealand
| | - Kunyu Li
- Department of Pathology, School of Medicine, University of Otago, Dunedin, New Zealand
| | - Kaisha Murray
- Dundee Cancer Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
| | - Tania Slatter
- Department of Pathology, School of Medicine, University of Otago, Dunedin, New Zealand.,Maurice Wilkins Centre for Biodiscovery, University of Otago, Dunedin, New Zealand
| | - Jean-Christophe Bourdon
- Dundee Cancer Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
| | - Antony W Braithwaite
- Department of Pathology, School of Medicine, University of Otago, Dunedin, New Zealand.,Maurice Wilkins Centre for Biodiscovery, University of Otago, Dunedin, New Zealand
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31
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Yun WB, Kim JE, Lee ML, Choi JY, Park JJ, Song BR, Kang BC, Nam KT, Lee HW, Hwang DY. Sensitivity to tumor development by TALEN-mediated Trp53 mutant genes in the susceptible FVB/N mice and the resistance C57BL/6 mice. Lab Anim Res 2021; 37:32. [PMID: 34839833 PMCID: PMC8628475 DOI: 10.1186/s42826-021-00107-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 10/12/2021] [Indexed: 11/29/2022] Open
Abstract
Background This study was undertaken to compare the sensitivities of mice strains during tumor induction by transcription activator-like effector nucleases (TALEN)-mediated Trp53 mutant gene. Alterations of their tumorigenic phenotypes including survival rate, tumor formation and tumor spectrum, were assessed in FVB/N-Trp53em2Hwl/Korl and C57BL/6-Trp53em1Hwl/Korl knockout (KO) mice over 16 weeks.
Results Most of the physiological phenotypes factors were observed to be higher in FVB/N-Trp53em2Hwl/Korl KO mice than C57BL/6-Trp53em1Hwl/Korl KO mice, although there were significant differences in the body weight, immune organ weight, number of red blood cells, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet count (PLT), total bilirubin (Bil-T) and glucose (Glu) levels in the KO mice relative to the wild type (WT) mice. Furthermore, numerous solid tumors were also observed in various regions of the surface skin of FVB/N-Trp53em2Hwl/Korl KO mice, but were not detected in C57BL/6-Trp53em1Hwl/Korl KO mice. The most frequently observed tumor in both the Trp53 KO mice was malignant lymphoma, while soft tissue teratomas and hemangiosarcomas were only detected in the FVB/N-Trp53em2Hwl/Korl KO mice. Conclusions Our results indicate that the spectrum and incidence of tumors induced by the TALEN-mediated Trp53 mutant gene is greater in FVB/N-Trp53em2Hwl/Korl KO mice than C57BL/6-Trp53em1Hwl/Korl KO mice over 16 weeks.
Supplementary Information The online version contains supplementary material available at 10.1186/s42826-021-00107-y.
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Affiliation(s)
- Woo Bin Yun
- Department of Biomaterials Science (BK21 FOUR Program), College of Natural Resources and Life Science, Pusan National University, 50 Cheonghak-ri, Samnangjin-eup, Miryang-si, Gyeongsangnam-do, 50463, Korea.,Severance Biomedical Science Institute, College of Medicine, Yonsei University, Seoul, 03722, South Korea
| | - Ji Eun Kim
- Department of Biomaterials Science (BK21 FOUR Program), College of Natural Resources and Life Science, Pusan National University, 50 Cheonghak-ri, Samnangjin-eup, Miryang-si, Gyeongsangnam-do, 50463, Korea
| | - Mi Lim Lee
- Department of Biomaterials Science (BK21 FOUR Program), College of Natural Resources and Life Science, Pusan National University, 50 Cheonghak-ri, Samnangjin-eup, Miryang-si, Gyeongsangnam-do, 50463, Korea
| | - Jun Young Choi
- Department of Biomaterials Science (BK21 FOUR Program), College of Natural Resources and Life Science, Pusan National University, 50 Cheonghak-ri, Samnangjin-eup, Miryang-si, Gyeongsangnam-do, 50463, Korea
| | - Jin Ju Park
- Department of Biomaterials Science (BK21 FOUR Program), College of Natural Resources and Life Science, Pusan National University, 50 Cheonghak-ri, Samnangjin-eup, Miryang-si, Gyeongsangnam-do, 50463, Korea
| | - Bo Ram Song
- Department of Biomaterials Science (BK21 FOUR Program), College of Natural Resources and Life Science, Pusan National University, 50 Cheonghak-ri, Samnangjin-eup, Miryang-si, Gyeongsangnam-do, 50463, Korea
| | - Byeong Cheol Kang
- Department of Experimental Animal Research, Biomedical Research Institute, Seoul National University College of Medicine, Seoul, 03080, Korea
| | - Ki Taek Nam
- Severance Biomedical Science Institute, College of Medicine, Yonsei University, Seoul, 03722, South Korea
| | - Han-Woong Lee
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Korea
| | - Dae Youn Hwang
- Department of Biomaterials Science (BK21 FOUR Program), College of Natural Resources and Life Science, Pusan National University, 50 Cheonghak-ri, Samnangjin-eup, Miryang-si, Gyeongsangnam-do, 50463, Korea.
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32
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Guo Y, Rall-Scharpf M, Bourdon JC, Wiesmüller L, Biber S. p53 isoforms differentially impact on the POLι dependent DNA damage tolerance pathway. Cell Death Dis 2021; 12:941. [PMID: 34645785 PMCID: PMC8514551 DOI: 10.1038/s41419-021-04224-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 09/17/2021] [Accepted: 09/27/2021] [Indexed: 12/22/2022]
Abstract
The recently discovered p53-dependent DNA damage tolerance (DDT) pathway relies on its biochemical activities in DNA-binding, oligomerization, as well as complex formation with the translesion synthesis (TLS) polymerase iota (POLι). These p53-POLι complexes slow down nascent DNA synthesis for safe, homology-directed bypass of DNA replication barriers. In this study, we demonstrate that the alternative p53-isoforms p53β, p53γ, Δ40p53α, Δ133p53α, and Δ160p53α differentially affect this p53-POLι-dependent DDT pathway originally described for canonical p53α. We show that the C-terminal isoforms p53β and p53γ, comprising a truncated oligomerization domain (OD), bind PCNA. Conversely, N-terminally truncated isoforms have a reduced capacity to engage in this interaction. Regardless of the specific loss of biochemical activities required for this DDT pathway, all alternative isoforms were impaired in promoting POLι recruitment to PCNA in the chromatin and in decelerating DNA replication under conditions of enforced replication stress after Mitomycin C (MMC) treatment. Consistent with this, all alternative p53-isoforms no longer stimulated recombination, i.e., bypass of endogenous replication barriers. Different from the other isoforms, Δ133p53α and Δ160p53α caused a severe DNA replication problem, namely fork stalling even in untreated cells. Co-expression of each alternative p53-isoform together with p53α exacerbated the DDT pathway defects, unveiling impaired POLι recruitment and replication deceleration already under unperturbed conditions. Such an inhibitory effect on p53α was particularly pronounced in cells co-expressing Δ133p53α or Δ160p53α. Notably, this effect became evident after the expression of the isoforms in tumor cells, as well as after the knockdown of endogenous isoforms in human hematopoietic stem and progenitor cells. In summary, mimicking the situation found to be associated with many cancer types and stem cells, i.e., co-expression of alternative p53-isoforms with p53α, carved out interference with p53α functions in the p53-POLι-dependent DDT pathway.
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Affiliation(s)
- Yitian Guo
- grid.6582.90000 0004 1936 9748Department of Obstetrics and Gynecology, Ulm University, Ulm, 89075 Germany
| | - Melanie Rall-Scharpf
- grid.6582.90000 0004 1936 9748Department of Obstetrics and Gynecology, Ulm University, Ulm, 89075 Germany
| | - Jean-Christophe Bourdon
- grid.8241.f0000 0004 0397 2876Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Dundee, UK
| | - Lisa Wiesmüller
- grid.6582.90000 0004 1936 9748Department of Obstetrics and Gynecology, Ulm University, Ulm, 89075 Germany
| | - Stephanie Biber
- grid.6582.90000 0004 1936 9748Department of Obstetrics and Gynecology, Ulm University, Ulm, 89075 Germany
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Lees A, Sessler T, McDade S. Dying to Survive-The p53 Paradox. Cancers (Basel) 2021; 13:3257. [PMID: 34209840 PMCID: PMC8268032 DOI: 10.3390/cancers13133257] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 06/18/2021] [Accepted: 06/24/2021] [Indexed: 12/13/2022] Open
Abstract
The p53 tumour suppressor is best known for its canonical role as "guardian of the genome", activating cell cycle arrest and DNA repair in response to DNA damage which, if irreparable or sustained, triggers activation of cell death. However, despite an enormous amount of work identifying the breadth of the gene regulatory networks activated directly and indirectly in response to p53 activation, how p53 activation results in different cell fates in response to different stress signals in homeostasis and in response to p53 activating anti-cancer treatments remains relatively poorly understood. This is likely due to the complex interaction between cell death mechanisms in which p53 has been activated, their neighbouring stressed or unstressed cells and the local stromal and immune microenvironment in which they reside. In this review, we evaluate our understanding of the burgeoning number of cell death pathways affected by p53 activation and how these may paradoxically suppress cell death to ensure tissue integrity and organismal survival. We also discuss how these functions may be advantageous to tumours that maintain wild-type p53, the understanding of which may provide novel opportunity to enhance treatment efficacy.
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Affiliation(s)
- Andrea Lees
- Patrick G Johnston Centre for Cancer Research, Queen’s University, Belfast BT9 7AE, UK;
| | | | - Simon McDade
- Patrick G Johnston Centre for Cancer Research, Queen’s University, Belfast BT9 7AE, UK;
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Pawge G, Khatik GL. p53 regulated senescence mechanism and role of its modulators in age-related disorders. Biochem Pharmacol 2021; 190:114651. [PMID: 34118220 DOI: 10.1016/j.bcp.2021.114651] [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] [Received: 04/05/2021] [Revised: 06/05/2021] [Accepted: 06/08/2021] [Indexed: 10/21/2022]
Abstract
Multiple co-morbidities are associated with age, and there is a need for the broad-spectrum drug to prevent multiple regimens that may cause an adverse effect in the geriatric population. Cellular senescence is a primary mechanism for ageing in various tissues. p53, a tumor suppressor protein, plays a significant role in forming DNA damage foci and post different stress responses. DNA damage foci can be transient or persistent that can progress to DNA-SCARS inducing senescence. p53 also plays a role in apoptosis and negative regulation of SASP. Few upstream targets like FOXO4, MDM2, MDM4, USP7 control the availability of p53 for apoptosis. Hence, the senolytic therapies, modulating p53 upstream targets, can be a good approach for preventing age-related disorders. This review discusses the insights on the role of p53 in the formation of DNA-SCARS, various upstream target proteins, and pathways involved in p53 regulation. Further, the review aimed to include recently discovered small molecules acting on these upstream targets, and those can be modified using medicinal chemistry approaches to give successful senotherapeutics.
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Affiliation(s)
- Girija Pawge
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research- Raebareli, New Transit Campus, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, Uttar Pradesh 226301, India
| | - Gopal L Khatik
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research- Raebareli, New Transit Campus, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, Uttar Pradesh 226301, India.
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Diţescu D, Istrate-Ofiţeru AM, Roşu GC, Iovan L, Liliac IM, Zorilă GL, Bălăşoiu M, Cercelaru L. Clinical and pathological aspects of condyloma acuminatum - review of literature and case presentation. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY = REVUE ROUMAINE DE MORPHOLOGIE ET EMBRYOLOGIE 2021; 62:369-383. [PMID: 35024725 PMCID: PMC8848243 DOI: 10.47162/rjme.62.2.03] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Condyloma acuminatum (CA) is a pathology caused by the human papillomavirus (HPV). It is manifested by the appearance of warts in the vulvar, pubic, and anorectal regions, but can occur in other areas. It is a common disease that can be prevented by using measures such as condoms or vaccine. Topical, local, pharmacological, surgical, and excisional therapy options are available for this pathology. Macroscopically, it appears as a vegetative tumor, with a single implantation base that branches towards the periphery, with a cauliflower appearance. CA is defined microscopically by acanthosis, parakeratosis, papillomatosis and koilocytosis. Immunohistochemical studies can detect the presence of various HPV strains or viral antigens and can emphasize certain specific characteristics; e.g., in the case presented in this study, we observed that the tumor had a fulminant evolution due to a strong vascular base identified with anti-cluster of differentiation (CD) 34 antibody, by the existence of epithelial cells with a high degree of cell proliferation, as evidenced by the anti-Ki67 antibody, the inactivation of the tumor suppressor gene and the appearance of immunolabeling for the anti-p53 antibody, by the strong immunoreactivity for p63 which reveals the existence of cells with dysplastic and neoplastic transformation potential, but also by detecting the immunolabeling for p16INK4a that is associated with the existence of HPV. Also, the tumor was immunoreactive for cytokeratin (CK) AE1/AE3, partially immunoreactive for CK5/6 in the basal layer and negative for CK7, which demonstrates the squamous epithelial origin of the described tumor. Subepithelial cells of the inflammatory system have been identified, such as macrophages immunolabeled with anti-CD68 antibody, T-lymphocytes immunolabeled with anti-CD3 antibody and rare B-lymphocytes immunolabeled with anti-CD20 antibody, which demonstrates the strong cellular response to remove the virus from the structure. Surgical and excisional treatment was helpful for the patient, because she was able to resume normal sexual activity and defecation, and on the other hand, microscopic studies showed the potential for malignant transformation of CA.
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Affiliation(s)
- Damian Diţescu
- Department of Histology, University of Medicine and Pharmacy of Craiova, Romania; ,
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Li H, Wang J, Huang K, Zhang T, Gao L, Yang S, Yi W, Niu Y, Liu H, Wang Z, Wang G, Tao K, Wang L, Cai K. Nkx2.5 Functions as a Conditional Tumor Suppressor Gene in Colorectal Cancer Cells via Acting as a Transcriptional Coactivator in p53-Mediated p21 Expression. Front Oncol 2021; 11:648045. [PMID: 33869046 PMCID: PMC8047315 DOI: 10.3389/fonc.2021.648045] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 03/15/2021] [Indexed: 12/12/2022] Open
Abstract
NK2 homeobox 5 (Nkx2.5), a homeobox-containing transcription factor, is associated with a spectrum of congenital heart diseases. Recently, Nkx2.5 was also found to be differentially expressed in several kinds of tumors. In colorectal cancer (CRC) tissue and cells, hypermethylation of Nkx2.5 was observed. However, the roles of Nkx2.5 in CRC cells have not been fully elucidated. In the present study, we assessed the relationship between Nkx2.5 and CRC by analyzing the expression pattern of Nkx2.5 in CRC samples and the adjacent normal colonic mucosa (NCM) samples, as well as in CRC cell lines. We found higher expression of Nkx2.5 in CRC compared with NCM samples. CRC cell lines with poorer differentiation also had higher expression of Nkx2.5. Although this expression pattern makes Nkx2.5 seem like an oncogene, in vitro and in vivo tumor suppressive effects of Nkx2.5 were detected in HCT116 cells by establishing Nkx2.5-overexpressed CRC cells. However, Nkx2.5 overexpression was incapacitated in SW480 cells. To further assess the mechanism, different expression levels and mutational status of p53 were observed in HCT116 and SW480 cells. The expression of p21WAF1/CIP1, a downstream antitumor effector of p53, in CRC cells depends on both expression level and mutational status of p53. Overexpressed Nkx2.5 could elevate the expression of p21WAF1/CIP1 only in CRC cells with wild-type p53 (HCT116), rather than in CRC cells with mutated p53 (SW480). Mechanistically, Nkx2.5 could interact with p53 and increase the transcription of p21WAF1/CIP1 without affecting the expression of p53. In conclusion, our findings demonstrate that Nkx2.5 could act as a conditional tumor suppressor gene in CRC cells with respect to the mutational status of p53. The tumor suppressive effect of Nkx2.5 could be mediated by its role as a transcriptional coactivator in wild-type p53-mediated p21WAF1/CIP1 expression.
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Affiliation(s)
- Huili Li
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiliang Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kun Huang
- Institution of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Zhang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lu Gao
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Sai Yang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wangyang Yi
- Department of General Surgery, The Second People’s Hospital of Jingmen, Jingmen, China
| | - Yanfeng Niu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongli Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zheng Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guobin Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kaixiong Tao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lin Wang
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kailin Cai
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Shah S, Pendleton E, Couture O, Broachwalla M, Kusper T, Alt LAC, Fay MJ, Chandar N. P53 regulation of osteoblast differentiation is mediated through specific microRNAs. Biochem Biophys Rep 2021; 25:100920. [PMID: 33553686 PMCID: PMC7859171 DOI: 10.1016/j.bbrep.2021.100920] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 01/08/2021] [Accepted: 01/12/2021] [Indexed: 12/17/2022] Open
Abstract
In order to understand the role of the p53 tumor suppressor gene in microRNA expression during osteoblast differentiation, we used a screen to identify microRNAs that were altered in a p53-dependent manner. MicroRNAs from MC3T3-E1 preosteoblasts were isolated from day 0 (undifferentiated) and day 4 (differentiating) and compared to a p53 deficient MC3T3-E1 line treated similarly. Overall, one fourth of all the microRNAs tested showed a reduction of 0.6 fold, and a similar number of them were increased 1.7 fold with differentiation. P53 deficiency caused 40% reduction in expression of microRNAs in differentiating cells, while a small percent (0.03%) showed an increase. Changes in microRNAs were validated using real-time PCR and two microRNAs were selected for further analysis (miR-34b and miR-140). These two microRNAs were increased significantly during differentiation but showed a dramatic reduction in expression in a p53 deficient state. Stable expression of miR-34b and miR-140 in MC3T3-E1 cells resulted in decreases in cell proliferation rates when compared to control cells. There was a 4-fold increase in p53 levels with miR-34b expression and a less dramatic increase with miR-140. Putative target binding sites for bone specific transcription factors, Runx2 and Osterix, were found for miR-34b, while Runx2, beta catenin and type 1 collagen were found to be miR-140 targets. Western blot analyses and functional assays for the transcription factors Runx2, Osterix and Beta-catenin confirmed microRNA specific interactions. These studies provide evidence that p53 mediated regulation of osteoblast differentiation can also occur through specific microRNAs such as miR-34b and miR-140 that also directly target important bone specific genes.
The p53 tumor suppressor gene regulates microRNA expression during in vitro osteoblast differentiation. miR34b and miR140 targets include several bone specific markers such as runx2, beta catenin, type 1 collagen and osterix. miR34b and miR140 overexpression inhibits osteoblast cell proliferation.
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Affiliation(s)
- Shivang Shah
- Department of Biochemistry, College of Graduate Studies, Midwestern University, 555, 31st, Street, Downers Grove, IL60515, USA
| | - Elisha Pendleton
- Department of Biochemistry, College of Graduate Studies, Midwestern University, 555, 31st, Street, Downers Grove, IL60515, USA
| | - Oliver Couture
- Department of Biochemistry, College of Graduate Studies, Midwestern University, 555, 31st, Street, Downers Grove, IL60515, USA
| | - Mustafa Broachwalla
- Department of Biochemistry, College of Graduate Studies, Midwestern University, 555, 31st, Street, Downers Grove, IL60515, USA
| | - Teresa Kusper
- Department of Biochemistry, College of Graduate Studies, Midwestern University, 555, 31st, Street, Downers Grove, IL60515, USA
| | - Lauren A C Alt
- Department of Biomedical Sciences, College of Graduate Studies, Midwestern University, 555, 31st, Street, Downers Grove, IL60515, USA
| | - Michael J Fay
- Department of Biomedical Sciences, College of Graduate Studies, Midwestern University, 555, 31st, Street, Downers Grove, IL60515, USA.,Department of Pharmacology, College of Graduate Studies, Midwestern University, 555, 31st, Street, Downers Grove, IL60515, USA
| | - Nalini Chandar
- Department of Biochemistry, College of Graduate Studies, Midwestern University, 555, 31st, Street, Downers Grove, IL60515, USA
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Abstract
Critical to tumor surveillance in eukaryotic cells is the ability to perceive and respond to DNA damage. p53, fulfills its role as "guardian of the genome" by either arresting cells in the cell cycle in order to allow time for repair of DNA damage or regulating a process of programmed cell death known as apoptosis. This process will eliminate cells that have suffered severe damage from intrinsic or extrinsic factors such as X-ray irradiation or chemotherapeutic drug treatments that include doxorubicin, etoposide, cisplatin, and methotrexate. Assays designed to specifically detect cells undergoing programmed cell death are essential in defining the tissue specific responses to tumor therapy treatment, tissue damage, or degenerative processes. This chapter will delineate the TUNEL (terminal deoxynucleotidyl transferase nick-end labeling) assay that is used for the rapid detection of 3' OH ends of DNA that are generated during apoptosis.
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Biber S, Pospiech H, Gottifredi V, Wiesmüller L. Multiple biochemical properties of the p53 molecule contribute to activation of polymerase iota-dependent DNA damage tolerance. Nucleic Acids Res 2020; 48:12188-12203. [PMID: 33166398 PMCID: PMC7708082 DOI: 10.1093/nar/gkaa974] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 10/05/2020] [Accepted: 10/09/2020] [Indexed: 11/29/2022] Open
Abstract
We have previously reported that p53 decelerates nascent DNA elongation in complex with the translesion synthesis (TLS) polymerase ι (POLι) which triggers a homology-directed DNA damage tolerance (DDT) pathway to bypass obstacles during DNA replication. Here, we demonstrate that this DDT pathway relies on multiple p53 activities, which can be disrupted by TP53 mutations including those frequently found in cancer tissues. We show that the p53-mediated DDT pathway depends on its oligomerization domain (OD), while its regulatory C-terminus is not involved. Mutation of residues S315 and D48/D49, which abrogate p53 interactions with the DNA repair and replication proteins topoisomerase I and RPA, respectively, and residues L22/W23, which disrupt formation of p53-POLι complexes, all prevent this DDT pathway. Our results demonstrate that the p53-mediated DDT requires the formation of a DNA binding-proficient p53 tetramer, recruitment of such tetramer to RPA-coated forks and p53 complex formation with POLι. Importantly, our mutational analysis demonstrates that transcriptional transactivation is dispensable for the POLι-mediated DDT pathway, which we show protects against DNA replication damage from endogenous and exogenous sources.
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Affiliation(s)
- Stephanie Biber
- Department of Obstetrics and Gynecology, Ulm University, Ulm 89075, Germany
| | - Helmut Pospiech
- Project group Biochemistry, Leibniz Institute on Aging - Fritz Lipmann Institute, D-07745 Jena, Germany.,Faculty of Biochemistry and Molecular Medicine, FIN-90014 University of Oulu, Finland
| | - Vanesa Gottifredi
- Cell Cycle and Genomic Stability Laboratory, Fundación Instituto Leloir, Buenos Aires C1405BWE, Argentina
| | - Lisa Wiesmüller
- Department of Obstetrics and Gynecology, Ulm University, Ulm 89075, Germany
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40
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Werner H, Laron Z. Role of the GH-IGF1 system in progression of cancer. Mol Cell Endocrinol 2020; 518:111003. [PMID: 32919021 DOI: 10.1016/j.mce.2020.111003] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/17/2020] [Accepted: 08/20/2020] [Indexed: 12/13/2022]
Abstract
Emerging evidence links the growth hormone (GH)-insulin-like growth factor-1 (IGF1) endocrine axis to cancer development. While this putative correlation is of major translational relevance, most clinical and epidemiological reports to date found no causal linkage between GH therapy and enhanced cancer risk. Thus, it is generally agreed that GH therapy constitutes a safe pharmacological intervention. The present review focuses on a number of issues in the area of GH-IGF1 action in cancer development. Emphasis is given to the idea that GH and IGF1 do not conform to the definition of oncogenic factors. Specifically, these hormones, even at high pharmacological doses, are unable to induce malignant transformation. However, the GH-IGF1 axis is capable of 'pushing' already transformed cells through the various phases of the cell cycle. Viral and cellular oncogenes require an intact IGF1 signaling pathway in order to elicit transformation; in other words, oncogenic agents adopt the IGF1 pathway. This universal mechanism of action of oncogenes has broad implications in oncology. Our review provides an in-depth analysis of the interplay between the GH-IGF1 axis and cancer genes, including tumor suppressors p53 and BRCA1. Finally, the safety of GH therapy in both children and adults needs further long-term follow-up studies.
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Affiliation(s)
- Haim Werner
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Yoran Institute for Human Genome Research, Tel Aviv University, Tel Aviv, Israel.
| | - Zvi Laron
- Endocrinology and Diabetes Research Unit, Schneider Children's Medical Center, Petah Tikva, Israel
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41
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Hou Y, Hou L, Liang Y, Zhang Q, Hong X, Wang Y, Huang X, Zhong T, Pang W, Xu C, Zhu L, Li L, Fang J, Meng X. The p53-inducible CLDN7 regulates colorectal tumorigenesis and has prognostic significance. Neoplasia 2020; 22:590-603. [PMID: 32992138 PMCID: PMC7522441 DOI: 10.1016/j.neo.2020.09.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 08/28/2020] [Accepted: 09/01/2020] [Indexed: 12/24/2022] Open
Abstract
Most colorectal cancer (CRC) are characterized by allele loss of the genes located on the short arm of chromosome 17 (17p13.1), including the tumor suppressor p53 gene. Although important, p53 is not the only driver of chromosome 17p loss. In this study, we explored the biological and prognostic significance of genes around p53 on 17p13.1 in CRC. The Cancer Genome Atlas (TCGA) were used to identify differentially expressed genes located between 1000 kb upstream and downstream of p53 gene. The function of CLDN7 was evaluated by both in vitro and in vivo experiments. Quantitative real-time PCR, western blot, and promoter luciferase activity, immunohistochemistry were used to explore the molecular drivers responsible for the development and progression of CRC. The results showed that CLDN7, located between 1000 kb upstream and downstream of p53 gene, were remarkably differentially expressed in tumor and normal tissues. CLDN7 expression also positively associated with p53 level in different stages of the adenoma-carcinoma sequence. Both in vitro and in vivo assays showed that CLDN7 inhibited cell proliferation in p53 wild type CRC cells, but had no effects on p53 mutant CRC cells. Mechanistically, p53 could bind to CLDN7 promoter region and regulate its expression. Clinically, high CLDN7 expression was negatively correlated with tumor size, invasion depth, lymphatic metastasis and AJCC III/IV stage, but was positively associated with favorable prognosis of CRC patients. Collectively, our work uncovers the tumor suppressive function for CLDN7 in a p53-dependent manner, which may mediate colorectal tumorigenesis induced by p53 deletion or mutation.
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Affiliation(s)
- Yichao Hou
- Department of Gastroenterology, Shanghai Nineth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Lidan Hou
- Department of Gastroenterology, Shanghai Nineth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Yu Liang
- Department of Gastroenterology, Shanghai Nineth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Qingwei Zhang
- Division of Gastroenterology and Hepatology, Key Laboratory Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai 200001, China
| | - Xialu Hong
- Division of Gastroenterology and Hepatology, Key Laboratory Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai 200001, China
| | - Yu Wang
- Department of Gastroenterology, Shanghai Nineth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Xin Huang
- Department of Gastroenterology, Shanghai Nineth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Ting Zhong
- Department of Gastroenterology, Shanghai Nineth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Wenjing Pang
- Department of Gastroenterology, Shanghai Nineth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Ci Xu
- Department of Gastroenterology, Shanghai Nineth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Liming Zhu
- Department of Gastroenterology, Shanghai Nineth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Lei Li
- Department of Gastroenterology, Shanghai Nineth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Jingyuan Fang
- Division of Gastroenterology and Hepatology, Key Laboratory Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai 200001, China.
| | - Xiangjun Meng
- Department of Gastroenterology, Shanghai Nineth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China.
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42
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p53 drives a transcriptional program that elicits a non-cell-autonomous response and alters cell state in vivo. Proc Natl Acad Sci U S A 2020; 117:23663-23673. [PMID: 32900967 DOI: 10.1073/pnas.2008474117] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Cell stress and DNA damage activate the tumor suppressor p53, triggering transcriptional activation of a myriad of target genes. The molecular, morphological, and physiological consequences of this activation remain poorly understood in vivo. We activated a p53 transcriptional program in mice by deletion of Mdm2, a gene that encodes the major p53 inhibitor. By overlaying tissue-specific RNA-sequencing data from pancreas, small intestine, ovary, kidney, and heart with existing p53 chromatin immunoprecipitation (ChIP) sequencing, we identified a large repertoire of tissue-specific p53 genes and a common p53 transcriptional signature of seven genes, which included Mdm2 but not p21 Global p53 activation caused a metaplastic phenotype in the pancreas that was missing in mice with acinar-specific p53 activation, suggesting non-cell-autonomous effects. The p53 cellular response at single-cell resolution in the intestine altered transcriptional cell state, leading to a proximal enterocyte population enriched for genes within oxidative phosphorylation pathways. In addition, a population of active CD8+ T cells was recruited. Combined, this study provides a comprehensive profile of the p53 transcriptional response in vivo, revealing both tissue-specific transcriptomes and a unique signature, which were integrated to induce both cell-autonomous and non-cell-autonomous responses and transcriptional plasticity.
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Tan Z, Zhu J, Stemmer PM, Sun L, Yang Z, Schultz K, Gaffrey MJ, Cesnik AJ, Yi X, Hao X, Shortreed MR, Shi T, Lubman DM. Comprehensive Detection of Single Amino Acid Variants and Evaluation of Their Deleterious Potential in a PANC-1 Cell Line. J Proteome Res 2020; 19:1635-1646. [PMID: 32058723 DOI: 10.1021/acs.jproteome.9b00840] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Identifying single amino acid variants (SAAVs) in cancer is critical for precision oncology. Several advanced algorithms are now available to identify SAAVs, but attempts to combine different algorithms and optimize them on large data sets to achieve a more comprehensive coverage of SAAVs have not been implemented. Herein, we report an expanded detection of SAAVs in the PANC-1 cell line using three different strategies, which results in the identification of 540 SAAVs in the mass spectrometry data. Among the set of 540 SAAVs, 79 are evaluated as deleterious SAAVs based on analysis using the novel AssVar software in which one of the driver mutations found in each protein of KRAS, TP53, and SLC37A4 is further validated using independent selected reaction monitoring (SRM) analysis. Our study represents the most comprehensive discovery of SAAVs to date and the first large-scale detection of deleterious SAAVs in the PANC-1 cell line. This work may serve as the basis for future research in pancreatic cancer and personal immunotherapy and treatment.
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Affiliation(s)
- Zhijing Tan
- Department of Surgery, The University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Jianhui Zhu
- Department of Surgery, The University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Paul M Stemmer
- Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan 48202, United States
| | - Liangliang Sun
- Department of Chemistry, Michigan State University, 578 South Shaw Lane, East Lansing, Michigan 48824, United States
| | - Zhichang Yang
- Department of Chemistry, Michigan State University, 578 South Shaw Lane, East Lansing, Michigan 48824, United States
| | - Kendall Schultz
- Integrative Omics Group, Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352, United States
| | - Matthew J Gaffrey
- Integrative Omics Group, Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352, United States
| | - Anthony J Cesnik
- Department of Genetics, Stanford University, Stanford, California 94305, United States
| | - Xinpei Yi
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, United States
| | - Xiaohu Hao
- Shanghai Institutes for Biological Science, Chinese Academy of Science, Shanghai 200031, China
| | - Michael R Shortreed
- Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States
| | - Tujin Shi
- Integrative Omics Group, Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352, United States
| | - David M Lubman
- Department of Surgery, The University of Michigan, Ann Arbor, Michigan 48109, United States
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p53 CRISPR Deletion Affects DNA Structure and Nuclear Architecture. J Clin Med 2020; 9:jcm9020598. [PMID: 32098416 PMCID: PMC7073688 DOI: 10.3390/jcm9020598] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 02/20/2020] [Accepted: 02/20/2020] [Indexed: 01/10/2023] Open
Abstract
The TP53 gene is a key tumor suppressor. Although the tumor suppressor p53 was one of the first to be characterized as a transcription factor, with its main function potentiated by its interaction with DNA, there are still many unresolved questions about its mechanism of action. Here, we demonstrate a novel role for p53 in the maintenance of nuclear architecture of cells. Using three-dimensional (3D) imaging and spectral karyotyping, as well as super resolution microscopy of DNA structure, we observe significant differences in 3D telomere signatures, DNA structure and DNA-poor spaces as well gains or losses of chromosomes, between normal and tumor cells with CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-deleted or wild-type TP53. Additionally, treatment with Nutlin-3 results in differences in nuclear architecture of telomeres in wild-type but not in p53 knockout MCF-7 (Michigan Cancer Foundation-7) cells. Nutlin-3 binds to the p53-binding pocket of mouse double minute 2 (MDM2) and blocks the p53-MDM2 interaction. Moreover, we demonstrate that another p53 stabilizing small molecule, RITA (reactivation of p53 and induction of tumor cell apoptosis), also induces changes in 3D DNA structure, apparently in a p53 independent manner. These results implicate p53 activity in regulating nuclear organization and, additionally, highlight the divergent effects of the p53 targeting compounds Nutlin-3 and RITA.
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Kose O, Rachidi W, Beal D, Erkekoglu P, Fayyad-Kazan H, Kocer Gumusel B. The effects of different bisphenol derivatives on oxidative stress, DNA damage and DNA repair in RWPE-1 cells: A comparative study. J Appl Toxicol 2019; 40:643-654. [PMID: 31875995 DOI: 10.1002/jat.3934] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Bisphenol A (BPA) is a well-known endocrine disruptor and it is widely used mainly in the plastics industry. Due to recent reports on its possible impact on health (particularly on the male reproductive system), bisphenol F (BPF) and bisphenol S (BPS) are now being used as alternatives. In this study, RWPE-1 cells were used as a model to compare cytotoxicity, oxidative stress-causing potential and genotoxicity of these chemicals. In addition, the effects of the bisphenol derivatives were assessed on DNA repair proteins. RWPE-1 cells were incubated with BPA, BPF, and BPS at concentrations of 0-600 μM for 24 h. The inhibitory concentration 20 (IC20 , concentration that causes 20% of cell viability loss) values for BPA, BPF, and BPS were 45, 65, and 108 μM, respectively. These results indicated that cytotoxicity potentials were ranked as BPA > BPF > BPS. We also found alterations in superoxide dismutase, glutathione peroxidase and glutathione reductase activities, and glutathione and total antioxidant capacity in all bisphenol-exposed groups. In the standard and modified Comet assay, BPS produced significantly higher levels of DNA damage vs the control. DNA repair proteins (OGG1, Ape-1, and MyH) involved in the base excision repair pathway, as well as p53 protein levels were down-regulated in all of the bisphenol-exposed groups. We found that the BPA alternatives were also cytotoxic and genotoxic, and changed the expressions of DNA repair enzymes. Therefore, further studies are needed to assess whether they can be used safely as alternatives to BPA or not.
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Affiliation(s)
- Ozge Kose
- Faculty of Pharmacy, Department of Toxicology, Sıhhiye, Hacettepe University, Ankara, Turkey
| | - Walid Rachidi
- Faculté de Médecine-Pharmacie¸ Domaine de la Merci, University Grenoble Alpes, Grenoble, France.,Commissariat à l'Énergie Atomique et aux Énergies Alternatives (CEA), Institut Nanosciences et Cryogénie (INAC), Systèmes Moléculaires et NanoMatériaux pour l'Energie et la Santé (SyMMES), Lésions des Acides Nucléiques (LAN), Grenoble, France
| | - David Beal
- Faculté de Médecine-Pharmacie¸ Domaine de la Merci, University Grenoble Alpes, Grenoble, France.,Commissariat à l'Énergie Atomique et aux Énergies Alternatives (CEA), Institut Nanosciences et Cryogénie (INAC), Systèmes Moléculaires et NanoMatériaux pour l'Energie et la Santé (SyMMES), Lésions des Acides Nucléiques (LAN), Grenoble, France
| | - Pınar Erkekoglu
- Faculty of Pharmacy, Department of Toxicology, Sıhhiye, Hacettepe University, Ankara, Turkey
| | - Hussein Fayyad-Kazan
- Faculty of Sciences I, Laboratory of Cancer Biology and Molecular Immunology, Lebanese University, Hadath, Lebanon
| | - Belma Kocer Gumusel
- Faculty of Pharmacy, Department of Toxicology, Lokman Hekim University, Ankara, Turkey
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Pitolli C, Wang Y, Mancini M, Shi Y, Melino G, Amelio I. Do Mutations Turn p53 into an Oncogene? Int J Mol Sci 2019; 20:E6241. [PMID: 31835684 PMCID: PMC6940991 DOI: 10.3390/ijms20246241] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 11/26/2019] [Accepted: 12/05/2019] [Indexed: 02/06/2023] Open
Abstract
The key role of p53 as a tumor suppressor became clear when it was realized that this gene is mutated in 50% of human sporadic cancers, and germline mutations expose carriers to cancer risk throughout their lifespan. Mutations in this gene not only abolish the tumor suppressive functions of p53, but also equip the protein with new pro-oncogenic functions. Here, we review the mechanisms by which these new functions gained by p53 mutants promote tumorigenesis.
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Affiliation(s)
- Consuelo Pitolli
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy; (C.P.); (M.M.); (G.M.)
- MRC Toxicology Unit, University of Cambridge, Pathology Building, Tennis Court Road, Cambridge CB2 1PQ, UK
| | - Ying Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 100012, China; (Y.W.); (Y.S.)
| | - Mara Mancini
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy; (C.P.); (M.M.); (G.M.)
- IDI-IRCCS, Biochemistry Laboratory, 00167 Rome, Italy
| | - Yufang Shi
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 100012, China; (Y.W.); (Y.S.)
- Institutes for Translational Medicine, Soochow University, Suzhou 215006, China
| | - Gerry Melino
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy; (C.P.); (M.M.); (G.M.)
- MRC Toxicology Unit, University of Cambridge, Pathology Building, Tennis Court Road, Cambridge CB2 1PQ, UK
| | - Ivano Amelio
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy; (C.P.); (M.M.); (G.M.)
- MRC Toxicology Unit, University of Cambridge, Pathology Building, Tennis Court Road, Cambridge CB2 1PQ, UK
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Natarajan P, Jaiswal S, Kathiresan S. Clonal Hematopoiesis: Somatic Mutations in Blood Cells and Atherosclerosis. CIRCULATION-GENOMIC AND PRECISION MEDICINE 2019; 11:e001926. [PMID: 29987111 DOI: 10.1161/circgen.118.001926] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The most important prognostic factor for atherosclerotic cardiovascular disease is age, independent of all other recognized risk factors. Recently, exome sequence analyses showed that somatic mutations in blood cells, a process termed clonal hematopoiesis, are common and increase in prevalence with age, with at least 1 in 10 adults older than 70 years affected. Carriers of clonal hematopoiesis have been shown to be not only at heightened risk for hematologic malignancy but also at increased risk for atherosclerotic cardiovascular disease. Here, we review the prior literature of clonal selection and expansion of hematopoietic stem cells and the evidence supporting its causal association with atherosclerotic cardiovascular disease.
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Affiliation(s)
- Pradeep Natarajan
- Center for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston (P.N., S.K.). .,Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA (P.N., S.K.).,Department of Medicine, Harvard Medical School, Boston, MA (P.N., S.K.)
| | - Siddhartha Jaiswal
- Center for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston (P.N., S.K.).,Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA (P.N., S.K.).,Department of Medicine, Harvard Medical School, Boston, MA (P.N., S.K.)
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Chen N, Hu Z, Yang Y, Han H, Lei H. Inactive Cas9 blocks vitreous-induced expression of Mdm2 and proliferation and survival of retinal pigment epithelial cells. Exp Eye Res 2019; 186:107716. [PMID: 31278903 DOI: 10.1016/j.exer.2019.107716] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 06/21/2019] [Accepted: 06/28/2019] [Indexed: 01/09/2023]
Abstract
Mouse double minute (MDM)2 single nucleotide polymorphism (SNP) 309G allele in the second promoter of MDM2 enhances vitreous-induced expression of Mdm2 and degradation of the tumor suppressor protein p53. This MDM2SNP309G contributes to certain cancer development and experimental proliferative vitreoretinopathy. The goal of this study is to discover a novel strategy to only block vitreous-induced expression of Mdm2 for preventing vitreous-induced cell proliferation and survival and thus find a potential novel strategy to treat proliferation-related diseases. We created two mutations (D10A and H840A) in Streptococcus pyogenes (Sp)Cas9 within the nuclease domains (RuvC1 and HNH, respectively) to render this SpCas9 nuclease dead named as dCas9 in a lentiCRISPR v2 vector. Then an MDM2-sgRNA targeting the second promoter of human MDM2 gene was cloned into this vector for producing lentivirus to infect human retinal pigment epithelial (RPE) cells with, which carry a heterozygous genotype of MDM2SNP309 T/G. lacZ-sgRNA was used as a control. As a result, we discovered that vitreous from experimental rabbits induced a 1.9 ± 0.2 fold increase in Mdm2 and a 2.0 ± 0.2 fold decrease in p53 in the RPE cells with dCas9/lacZ-sgRNA compared to those with dCas9/MDM2-sgRNA, suggesting that dCas9 under the guidance of the MDM2-sgRNA prevented RV-stimulated increase in Mdm2. In addition, we found that the rabbit vitreous significantly enhanced cell proliferation (1.5 ± 0.2 fold), survival against apoptosis (2.2 ± 0.2 fold), migration (10 ± 1.5%) and contraction (112.7 ± 14.1 mm2) of the cells with dCas9/lacZ-sgRNA compared with those with dCas9/MDM2-sgRNA. These results indicated that application of the dCas9 targeted to the P2 of MDM2 is a potential therapeutic approach to diseases due to the P2-driven aberrant expression of Mdm2 - such as proliferative vitreoretinopathy.
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Affiliation(s)
- Na Chen
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; Department of Ophthalmology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, PR China
| | - Zhengping Hu
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Yanhui Yang
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Haote Han
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Hetian Lei
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
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Bewersdorf JP, Ardasheva A, Podoltsev NA, Singh A, Biancon G, Halene S, Zeidan AM. From clonal hematopoiesis to myeloid leukemia and what happens in between: Will improved understanding lead to new therapeutic and preventive opportunities? Blood Rev 2019; 37:100587. [DOI: 10.1016/j.blre.2019.100587] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Revised: 06/22/2019] [Accepted: 07/02/2019] [Indexed: 02/08/2023]
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50
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Cheon MG, Son YW, Lee JH, Jang HH, Chung YS. Mts1 Up-regulation is Associated With Aggressive Pathological Features in Thyroid Cancer. Cancer Genomics Proteomics 2019; 16:369-376. [PMID: 31467231 DOI: 10.21873/cgp.20142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 06/28/2019] [Accepted: 07/01/2019] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND/AIM Thyroid cancer is the most common type of endocrine cancer and its incidence and mortality are increasing. However, few studies on the molecular factors related to its poor prognosis have been performed. The aim of our study was to identify a poor prognostic factor for thyroid cancer to reduce its overtreatment, recurrence, and mortality. MATERIALS AND METHODS The present study is a retrospective study of 55 patients who were diagnosed with papillary thyroid cancer and operated in Korea from September 2013 to November 2015. RESULTS Mts1 is a member of the S100 protein family and is involved in tumor progression and metastasis. Mts1 was highly expressed in patients with thyroid cancer and high Mts1 levels were related to poor prognoses such as lymph node metastasis. CONCLUSION Mts1 is associated with aggressive pathological features in thyroid cancer, and may be a poor prognostic factor for thyroid cancer.
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Affiliation(s)
- Min Gyeong Cheon
- Department of Biochemistry, College of Medicine, Gachon University, Incheon, Republic of Korea
| | - Ye Won Son
- Department of Biochemistry, College of Medicine, Gachon University, Incheon, Republic of Korea
| | - Joon-Hyop Lee
- Department of Surgery, Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Ho Hee Jang
- Department of Biochemistry, College of Medicine, Gachon University, Incheon, Republic of Korea
| | - Yoo Seung Chung
- Department of Surgery, Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of Korea
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