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1
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Moeckel C, Gaydosh L, Schneper L, Mitchell C, Notterman DA. Material hardship and telomere length in children. Child Dev 2024; 95:2232-2240. [PMID: 38943658 PMCID: PMC11579632 DOI: 10.1111/cdev.14126] [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] [Indexed: 07/01/2024]
Abstract
Telomere length (TL) serves as a biomarker of exposure to stressors, including material hardship. Data from the Future of Families and Child Wellbeing Study (1998-2015) were utilized to determine whether prior material hardship was associated with shorter salivary TL at years 9 and 15. 49% of the year 9 study population were female, 49% were Black, and 25% were Hispanic. At year 9 (N = 1990), regression analyses found a significant association between prior material hardship and shorter TL (β = -.005, p < .01). Additionally, at year 15 (N = 1874), material hardship experienced during infancy and toddlerhood was associated with shorter TL (β = -.009, p < .01), pointing toward infancy and toddlerhood as a sensitive period.
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Affiliation(s)
- Camille Moeckel
- Princeton UniversityPrincetonNew JerseyUSA
- Penn State College of MedicineHersheyPennsylvaniaUSA
| | - Lauren Gaydosh
- The University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
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2
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Li Y, Tian X, Luo J, Bao T, Wang S, Wu X. Molecular mechanisms of aging and anti-aging strategies. Cell Commun Signal 2024; 22:285. [PMID: 38790068 PMCID: PMC11118732 DOI: 10.1186/s12964-024-01663-1] [Citation(s) in RCA: 42] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Accepted: 05/15/2024] [Indexed: 05/26/2024] Open
Abstract
Aging is a complex and multifaceted process involving a variety of interrelated molecular mechanisms and cellular systems. Phenotypically, the biological aging process is accompanied by a gradual loss of cellular function and the systemic deterioration of multiple tissues, resulting in susceptibility to aging-related diseases. Emerging evidence suggests that aging is closely associated with telomere attrition, DNA damage, mitochondrial dysfunction, loss of nicotinamide adenine dinucleotide levels, impaired macro-autophagy, stem cell exhaustion, inflammation, loss of protein balance, deregulated nutrient sensing, altered intercellular communication, and dysbiosis. These age-related changes may be alleviated by intervention strategies, such as calorie restriction, improved sleep quality, enhanced physical activity, and targeted longevity genes. In this review, we summarise the key historical progress in the exploration of important causes of aging and anti-aging strategies in recent decades, which provides a basis for further understanding of the reversibility of aging phenotypes, the application prospect of synthetic biotechnology in anti-aging therapy is also prospected.
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Affiliation(s)
- Yumeng Li
- Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences; National Center of Technology Innovation for Synthetic Biology, Tianjin, China
| | - Xutong Tian
- Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences; National Center of Technology Innovation for Synthetic Biology, Tianjin, China
| | - Juyue Luo
- Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences; National Center of Technology Innovation for Synthetic Biology, Tianjin, China
| | - Tongtong Bao
- Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences; National Center of Technology Innovation for Synthetic Biology, Tianjin, China
| | - Shujin Wang
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Xin Wu
- Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences; National Center of Technology Innovation for Synthetic Biology, Tianjin, China.
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3
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Li HY, Zheng LL, Hu N, Wang ZH, Tao CC, Wang YR, Liu Y, Aizimuaji Z, Wang HW, Zheng RQ, Xiao T, Rong WQ. Telomerase-related advances in hepatocellular carcinoma: A bibliometric and visual analysis. World J Gastroenterol 2024; 30:1224-1236. [PMID: 38577190 PMCID: PMC10989492 DOI: 10.3748/wjg.v30.i9.1224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 01/03/2024] [Accepted: 02/03/2024] [Indexed: 03/06/2024] Open
Abstract
BACKGROUND As a critical early event in hepatocellular carcinogenesis, telomerase activation might be a promising and critical biomarker for hepatocellular carcinoma (HCC) patients, and its function in the genesis and treatment of HCC has gained much attention over the past two decades. AIM To perform a bibliometric analysis to systematically assess the current state of research on HCC-related telomerase. METHODS The Web of Science Core Collection and PubMed were systematically searched to retrieve publications pertaining to HCC/telomerase limited to "articles" and "reviews" published in English. A total of 873 relevant publications related to HCC and telomerase were identified. We employed the Bibliometrix package in R to extract and analyze the fundamental information of the publications, such as the trends in the publications, citation counts, most prolific or influential writers, and most popular journals; to screen for keywords occurring at high frequency; and to draw collaboration and cluster analysis charts on the basis of coauthorship and co-occurrences. VOSviewer was utilized to compile and visualize the bibliometric data. RESULTS A surge of 51 publications on HCC/telomerase research occurred in 2016, the most productive year from 1996 to 2023, accompanied by the peak citation count recorded in 2016. Up to December 2023, 35226 citations were made to all publications, an average of 46.6 citations to each paper. The United States received the most citations (n = 13531), followed by China (n = 7427) and Japan (n = 5754). In terms of national cooperation, China presented the highest centrality, its strongest bonds being to the United States and Japan. Among the 20 academic institutions with the most publications, ten came from China and the rest of Asia, though the University of Paris Cité, Public Assistance-Hospitals of Paris, and the National Institute of Health and Medical Research (INSERM) were the most prolific. As for individual contributions, Hisatomi H, Kaneko S, and Ide T were the three most prolific authors. Kaneko S ranked first by H-index, G-index, and overall publication count, while Zucman-Rossi J ranked first in citation count. The five most popular journals were the World Journal of Gastroenterology, Hepatology, Journal of Hepatology, Oncotarget, and Oncogene, while Nature Genetics, Hepatology, and Nature Reviews Disease Primers had the most citations. We extracted 2293 keywords from the publications, 120 of which appeared more than ten times. The most frequent were HCC, telomerase and human telomerase reverse transcriptase (hTERT). Keywords such as mutational landscape, TERT promoter mutations, landscape, risk, and prognosis were among the most common issues in this field in the last three years and may be topics for research in the coming years. CONCLUSION Our bibliometric analysis provides a comprehensive overview of HCC/telomerase research and insights into promising upcoming research.
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Affiliation(s)
- Hai-Yang Li
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Lin-Lin Zheng
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Nan Hu
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zhi-Hao Wang
- Department of Hepatobiliary Hernia Surgery, Liaocheng Dongcangfu People’s Hospital, Liaocheng 252000, Shandong Province, China
| | - Chang-Cheng Tao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ya-Ru Wang
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yue Liu
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zulihumaer Aizimuaji
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Hong-Wei Wang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Rui-Qi Zheng
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ting Xiao
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Wei-Qi Rong
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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4
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Lyons CE, Razzoli M, Bartolomucci A. The impact of life stress on hallmarks of aging and accelerated senescence: Connections in sickness and in health. Neurosci Biobehav Rev 2023; 153:105359. [PMID: 37586578 PMCID: PMC10592082 DOI: 10.1016/j.neubiorev.2023.105359] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 07/03/2023] [Accepted: 08/10/2023] [Indexed: 08/18/2023]
Abstract
Chronic stress is a risk factor for numerous aging-related diseases and has been shown to shorten lifespan in humans and other social mammals. Yet how life stress causes such a vast range of diseases is still largely unclear. In recent years, the impact of stress on health and aging has been increasingly associated with the dysregulation of the so-called hallmarks of aging. These are basic biological mechanisms that influence intrinsic cellular functions and whose alteration can lead to accelerated aging. Here, we review correlational and experimental literature (primarily focusing on evidence from humans and murine models) on the contribution of life stress - particularly stress derived from adverse social environments - to trigger hallmarks of aging, including cellular senescence, sterile inflammation, telomere shortening, production of reactive oxygen species, DNA damage, and epigenetic changes. We also evaluate the validity of stress-induced senescence and accelerated aging as an etiopathological proposition. Finally, we highlight current gaps of knowledge and future directions for the field, and discuss perspectives for translational geroscience.
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Affiliation(s)
- Carey E Lyons
- Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA; Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, USA
| | - Maria Razzoli
- Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA
| | - Alessandro Bartolomucci
- Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA; Department of Medicine and Surgery, University of Parma, Parma, Italy.
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5
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Sun C, Bai S, Liang Y, Liu D, Liao J, Chen Y, Zhao X, Wu B, Huang D, Chen M, Wu D. The role of Sirtuin 1 and its activators in age-related lung disease. Biomed Pharmacother 2023; 162:114573. [PMID: 37018986 DOI: 10.1016/j.biopha.2023.114573] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/10/2023] [Accepted: 03/21/2023] [Indexed: 04/05/2023] Open
Abstract
Aging is a major driving factor in lung diseases. Age-related lung disease is associated with downregulated expression of SIRT1, an NAD+-dependent deacetylase that regulates inflammation and stress resistance. SIRT1 acts by inducing the deacetylation of various substrates and regulates several mechanisms that relate to lung aging, such as genomic instability, lung stem cell exhaustion, mitochondrial dysfunction, telomere shortening, and immune senescence. Chinese herbal medicines have many biological activities, exerting anti-inflammatory, anti-oxidation, anti-tumor, and immune regulatory effects. Recent studies have confirmed that many Chinese herbs have the effect of activating SIRT1. Therefore, we reviewed the mechanism of SIRT1 in age-related lung disease and explored the potential roles of Chinese herbs as SIRT1 activators in the treatment of age-related lung disease.
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6
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Armstrong E, Boonekamp J. Does oxidative stress shorten telomeres in vivo? A meta-analysis. Ageing Res Rev 2023; 85:101854. [PMID: 36657619 DOI: 10.1016/j.arr.2023.101854] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 12/18/2022] [Accepted: 01/15/2023] [Indexed: 01/18/2023]
Abstract
Telomere attrition is considered a hallmark of ageing. Untangling the proximate causes of telomere attrition may therefore reveal important aspects about the ageing process. In a landmark paper in 2002 Thomas von Zglinicki demonstrated that oxidative stress accelerates telomere attrition in cell culture. In the next 20 years, oxidative stress became firmly embedded into modern theories of ageing and telomere attrition. However, a recent surge of in vivo studies reveals an inconsistent pattern questioning the unequivocal role of oxidative stress in telomere length and telomere attrition (henceforth referred to as telomere dynamics), in living organisms. Here we report the results of the first formal meta-analysis on the association between oxidative stress and telomere dynamics in vivo, representing 37 studies, 4969 individuals, and 18,677 correlational measurements. The overall correlation between oxidative stress markers and telomere dynamics was indistinguishable from zero (r = 0.027). This result was independent of the type of oxidative stress marker, telomere dynamic, or taxonomic group. However, telomere measurement method affected the analysis and the subset of TRF-based studies showed a significant overall correlation (r = 0.09), supporting the prediction that oxidative stress accelerates telomere attrition. The correlation was more pronounced in short-lived species and during the adult life phase, when ageing becomes apparent. We then performed an additional meta-analysis of interventional studies (n = 7) manipulating oxidative stress. This revealed a significant effect of treatment on telomere dynamics (d=0.36). Our findings provide new support for the hypothesis that oxidative stress causes telomere attrition in living organisms.
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Affiliation(s)
- Emma Armstrong
- School of Biodiversity, One Health & Veterinary Medicine, University of Glasgow, Glasgow, United Kingdom; The Roslin Institute, The University of Edinburgh, Easter Bush Campus, Midlothian, United Kingdom
| | - Jelle Boonekamp
- School of Biodiversity, One Health & Veterinary Medicine, University of Glasgow, Glasgow, United Kingdom.
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7
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McKinney AM, Mathur R, Stevers NO, Molinaro AM, Chang SM, Phillips JJ, Costello JF. GABP couples oncogene signaling to telomere regulation in TERT promoter mutant cancer. Cell Rep 2022; 40:111344. [PMID: 36130485 PMCID: PMC9534059 DOI: 10.1016/j.celrep.2022.111344] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 06/17/2022] [Accepted: 08/22/2022] [Indexed: 11/05/2022] Open
Abstract
Telomerase activation counteracts senescence and telomere erosion caused by uncontrolled proliferation. Epidermal growth factor receptor (EGFR) amplification drives proliferation while telomerase reverse transcriptase promoter (TERTp) mutations underlie telomerase reactivation through recruitment of GA-binding protein (GABP). EGFR amplification and TERTp mutations typically co-occur in glioblastoma, the most common and aggressive primary brain tumor. To determine if these two frequent alterations driving proliferation and immortality are functionally connected, we combine analyses of copy number, mRNA, and protein data from tumor tissue with pharmacologic and genetic perturbations. We demonstrate that proliferation arrest decreases TERT expression in a GABP-dependent manner and elucidate a critical proliferation-to-immortality pathway from EGFR to TERT expression selectively from the mutant TERTp through activation of AMP-mediated kinase (AMPK) and GABP upregulation. EGFR-AMPK signaling promotes telomerase activity and maintains telomere length. These results define how the tumor cell immortality mechanism keeps pace with persistent oncogene signaling and cell cycling. TERT promoter mutations are common in human cancer and confer cellular immortality. McKinney et al. describe the interaction between TERT promoter mutations, EGFR amplification, and the cell cycle in glioblastoma. The results demonstrate how proliferation drivers cooperate with telomere maintenance mechanisms to counteract telomere shortening caused by unlimited cell division.
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Affiliation(s)
- Andrew M McKinney
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Radhika Mathur
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Nicholas O Stevers
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Annette M Molinaro
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Susan M Chang
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Joanna J Phillips
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Joseph F Costello
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
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8
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Guan L, Crasta KC, Maier AB. Assessment of cell cycle regulators in human peripheral blood cells as markers of cellular senescence. Ageing Res Rev 2022; 78:101634. [PMID: 35460888 DOI: 10.1016/j.arr.2022.101634] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 04/11/2022] [Accepted: 04/15/2022] [Indexed: 12/12/2022]
Abstract
Cellular senescence has gained increasing interest during recent years, particularly due to causal involvement in the aging process corroborated by multiple experimental findings. Indeed, cellular senescence considered to be one of the hallmarks of aging, is defined as a stable growth arrest predominantly mediated by cell cycle regulators p53, p21 and p16. Senescent cells have frequently been studied in the peripheral blood of humans due to its accessibility. This review summarizes ex vivo studies describing cell cycle regulators as markers of senescence in human peripheral blood cells, along with detection methodologies and associative studies examining demographic and clinical characteristics. The utility of techniques such as the quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), microarray, RNA sequencing and nCounter technologies for detection at the transcriptional level, along with Western blotting, enzyme-linked immunosorbent assay and flow cytometry at the translational level, will be brought up at salient points throughout this review. Notably, housekeeping genes or proteins serving as controls such as GAPDH and β-Actin, were found not to be stably expressed in some contexts. As such, optimization and validation of such genes during experimental design were recommended. In addition, the expression of cell cycle regulators was found to vary not only between different types of blood cells such as T cells and B cells but also between stages of cellular differentiation such as naïve T cells and highly differentiated T cells. On the other hand, the associations of the presence of cell cycle regulators with demographics (age, gender, ethnicity, and socioeconomic status), clinical characteristics (body mass index, specific diseases, disease-related parameters) and lifestyle vary in groups of participants. One envisions that increased understanding and insights into the assessment of cell cycle regulators as markers of senescence in human peripheral blood cells will help inform prognostication and clinical intervention in elderly individuals.
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Affiliation(s)
- Lihuan Guan
- Department of Medicine and Aged Care, @AgeMelbourne, The Royal Melbourne Hospital, The University of Melbourne, Victoria, Australia.
| | - Karen C Crasta
- Healthy Longevity Translational Researc h Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Physiology, National University of Singapore, Singapore; NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Agency for Science, Technology & Research (A⁎STAR), Institute of Molecular and Cell Biology (IMCB), Singapore.
| | - Andrea B Maier
- Department of Medicine and Aged Care, @AgeMelbourne, The Royal Melbourne Hospital, The University of Melbourne, Victoria, Australia; Healthy Longevity Translational Researc h Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Centre for Healthy Longevity, @AgeSingapore, National University Health System, Singapore; Department of Human Movement Sciences, @AgeAmsterdam, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, the Netherlands.
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9
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Zhou Z, Li Y, Xu H, Xie X, He Z, Lin S, Li R, Jin S, Cui J, Hu H, Liu F, Wu S, Ma W, Songyang Z. An inducible CRISPR/Cas9 screen identifies DTX2 as a transcriptional regulator of human telomerase. iScience 2022; 25:103813. [PMID: 35198878 PMCID: PMC8844827 DOI: 10.1016/j.isci.2022.103813] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 12/07/2021] [Accepted: 01/20/2022] [Indexed: 01/12/2023] Open
Abstract
Most tumor cells reactivate telomerase to ensure unlimited proliferation, whereas the expression of human telomerase reverse transcriptase (hTERT) is tightly regulated and rate-limiting for telomerase activity maintenance. Several general transcription factors (TFs) have been found in regulating hTERT transcription; however, a systematic study is lacking. Here we performed an inducible CRISPR/Cas9 KO screen using an hTERT core promoter-driven reporter. We identified numerous positive regulators including an E3 ligase DTX2. In telomerase-positive cancer cells, DTX2 depletion downregulated hTERT transcription and telomerase activity, contributing to progressive telomere shortening, growth arrest, and increased apoptosis. Utilizing BioID, we characterized multiple TFs as DTX2 proximal proteins, among which NFIC functioned corporately with DTX2 in promoting hTERT transcription. Further analysis demonstrated that DTX2 mediated K63-linked ubiquitination of NFIC, which facilitated NFIC binding to the hTERT promoter and enhanced hTERT expression. These findings highlight a new hTERT regulatory pathway that may be exploited for potential cancer therapeutics.
An inducible CRISPR/Cas9 screen identifies regulators for hTERT transcription DTX2 deficiency leads to telomere shortening and cell growth arrest DTX2 mediates ubiquitination on NFIC, stabilizing NFIC binding on hTERT promoter DTX2-NFIC functions corporately to promote hTERT transcription and tumorigenesis
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Affiliation(s)
- Zhifen Zhou
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, Guangzhou Key Laboratory of Healthy Aging Research, Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
| | - Yujing Li
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, Guangzhou Key Laboratory of Healthy Aging Research, Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
| | - Huimin Xu
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, Guangzhou Key Laboratory of Healthy Aging Research, Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
| | - Xiaowei Xie
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, Guangzhou Key Laboratory of Healthy Aging Research, Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
| | - Zibin He
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, Guangzhou Key Laboratory of Healthy Aging Research, Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
| | - Song Lin
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, Guangzhou Key Laboratory of Healthy Aging Research, Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
| | - Ruofei Li
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, Guangzhou Key Laboratory of Healthy Aging Research, Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
| | - Shouheng Jin
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, Guangzhou Key Laboratory of Healthy Aging Research, Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
| | - Jun Cui
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, Guangzhou Key Laboratory of Healthy Aging Research, Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
| | - Hai Hu
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Feng Liu
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, Guangzhou Key Laboratory of Healthy Aging Research, Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
| | - Su Wu
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, Guangzhou Key Laboratory of Healthy Aging Research, Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
- Corresponding author
| | - Wenbin Ma
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, Guangzhou Key Laboratory of Healthy Aging Research, Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
- Corresponding author
| | - Zhou Songyang
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, Guangzhou Key Laboratory of Healthy Aging Research, Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510005, China
- Corresponding author
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10
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Faniyi AA, Hughes MJ, Scott A, Belchamber KBR, Sapey E. Inflammation, Ageing and Diseases of the Lung: Potential therapeutic strategies from shared biological pathways. Br J Pharmacol 2021; 179:1790-1807. [PMID: 34826882 DOI: 10.1111/bph.15759] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 10/07/2021] [Accepted: 11/08/2021] [Indexed: 12/15/2022] Open
Abstract
Lung diseases disproportionately affect elderly individuals. The lungs form a unique environment: a highly elastic organ with gaseous exchange requiring the closest proximity of inhaled air containing harmful agents and the circulating blood volume. The lungs are highly susceptible to senescence, with age and "inflammageing" creating a pro-inflammatory environment with a reduced capacity to deal with challenges. Whilst lung diseases may have disparate causes, the burden of ageing and inflammation provides a common process which can exacerbate seemingly unrelated pathologies. However, these shared pathways may also provide a common route to treatment, with increased interest in drugs which target ageing processes across respiratory diseases. In this review, we will examine the evidence for the increased burden of lung disease in older adults, the structural and functional changes seen with advancing age and assess what our expanding knowledge of inflammation and ageing pathways could mean for the treatment of lung disease.
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Affiliation(s)
- A A Faniyi
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, U.K
| | - M J Hughes
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, U.K
| | - A Scott
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, U.K
| | - K B R Belchamber
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, U.K
| | - E Sapey
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, U.K
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11
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Evans JR, Torres-Pérez JV, Miletto Petrazzini ME, Riley R, Brennan CH. Stress reactivity elicits a tissue-specific reduction in telomere length in aging zebrafish (Danio rerio). Sci Rep 2021; 11:339. [PMID: 33431974 PMCID: PMC7801459 DOI: 10.1038/s41598-020-79615-1] [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: 09/01/2020] [Accepted: 11/26/2020] [Indexed: 01/29/2023] Open
Abstract
Individual differences in personality are associated with variation in healthy aging. Health behaviours are often cited as the likely explanation for this association; however, an underlying biological mechanism may also exist. Accelerated leukocyte telomere shortening is implicated in multiple age-related diseases and is associated with chronic activation of the hypothalamus-pituitary-adrenal (HPA) axis, providing a link between stress-related personality differences and adverse health outcomes. However, the effects of the HPA axis are tissue specific. Thus, leukocyte telomere length may not accurately reflect telomere length in disease-relevant tissues. Here, we examined the correlation between stress reactivity and telomere length in heart and brain tissue in young (6-9 month) and aging (18 month) zebrafish. Stress reactivity was assessed by tank diving and through gene expression. Telomere length was assessed using quantitative PCR. We show that aging zebrafish have shorter telomeres in both heart and brain. Telomere length was inversely related to stress reactivity in heart but not brain of aging individuals. These data support the hypotheses that an anxious predisposition contributes to accelerated telomere shortening in heart tissue, which may have important implications for our understanding of age-related heart disease, and that stress reactivity contributes to age-related telomere shortening in a tissue-specific manner.
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Affiliation(s)
- James R. Evans
- grid.4868.20000 0001 2171 1133School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Rd, London, E1 4NS UK
| | - Jose V. Torres-Pérez
- grid.4868.20000 0001 2171 1133School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Rd, London, E1 4NS UK
| | - Maria Elena Miletto Petrazzini
- grid.4868.20000 0001 2171 1133School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Rd, London, E1 4NS UK ,grid.5608.b0000 0004 1757 3470Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/B, 35131 Padova, Italy
| | - Riva Riley
- grid.4868.20000 0001 2171 1133School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Rd, London, E1 4NS UK
| | - Caroline H. Brennan
- grid.4868.20000 0001 2171 1133School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Rd, London, E1 4NS UK
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12
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Engin AB, Engin A. The Connection Between Cell Fate and Telomere. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1275:71-100. [PMID: 33539012 DOI: 10.1007/978-3-030-49844-3_3] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Abolition of telomerase activity results in telomere shortening, a process that eventually destabilizes the ends of chromosomes, leading to genomic instability and cell growth arrest or death. Telomere shortening leads to the attainment of the "Hayflick limit", and the transition of cells to state of senescence. If senescence is bypassed, cells undergo crisis through loss of checkpoints. This process causes massive cell death concomitant with further telomere shortening and spontaneous telomere fusions. In functional telomere of mammalian cells, DNA contains double-stranded tandem repeats of TTAGGG. The Shelterin complex, which is composed of six different proteins, is required for the regulation of telomere length and stability in cells. Telomere protection by telomeric repeat binding protein 2 (TRF2) is dependent on DNA damage response (DDR) inhibition via formation of T-loop structures. Many protein kinases contribute to the DDR activated cell cycle checkpoint pathways, and prevent DNA replication until damaged DNA is repaired. Thereby, the connection between cell fate and telomere length-associated telomerase activity is regulated by multiple protein kinase activities. Contrarily, inactivation of DNA damage checkpoint protein kinases in senescent cells can restore cell-cycle progression into S phase. Therefore, telomere-initiated senescence is a DNA damage checkpoint response that is activated with a direct contribution from dysfunctional telomeres. In this review, in addition to the above mentioned, the choice of main repair pathways, which comprise non-homologous end joining and homologous recombination in telomere uncapping telomere dysfunctions, are discussed.
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Affiliation(s)
- Ayse Basak Engin
- Department of Toxicology, Faculty of Pharmacy, Gazi University, Ankara, Turkey.
| | - Atilla Engin
- Department of General Surgery, Faculty of Medicine, Gazi University, Ankara, Turkey
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13
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Fundamental insights into the interaction between telomerase/TERT and intracellular signaling pathways. Biochimie 2020; 181:12-24. [PMID: 33232793 DOI: 10.1016/j.biochi.2020.11.015] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 11/07/2020] [Accepted: 11/16/2020] [Indexed: 12/12/2022]
Abstract
Telomerase activity is critical for cancer cells to provide unrestricted proliferation and cellular immortality through maintaining telomeres. Telomerase enzymatic activity is regulatable at the level of DNA, mRNA, post translational modifications, cellular transport and enzyme assembly. More recent studies confirm the interaction of the telomerase with various intracellular signaling pathways including PI3K/AKT/mTOR, NF-κB and Wnt/β-catenin which mainly participating in inflammation, epithelial to mesenchymal transition (EMT) and tumor cell invasion and metastasis. Furthermore, hTERT protein has been detected in non-nuclear sites such as the mitochondria and cytoplasm in cells. Mitochondrial TERT indicates various non-telomere-related functions such as decreasing reactive oxygen species (ROS) generation, boosting the respiration rate, protecting mtDNA by direct binding, interacting with mitochondrial tRNAs and increasing mitochondrial membrane potential which can lead to higher chemoresistance rate in cancer cells during therapies. Understanding the molecular mechanisms of the TERT function and depended interactions in tumor cells can suggest novel therapeutic approaches. Hence, in this review we will explain the telomerase activity regulation in translational and post translational levels besides the established correlations with various cell signaling pathways with possible pathways for therapeutic targeting.
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14
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Non-esterified fatty acids and telomere length in older adults: The Cardiovascular Health Study. Metabol Open 2020; 8:100058. [PMID: 32995737 PMCID: PMC7502331 DOI: 10.1016/j.metop.2020.100058] [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: 06/03/2020] [Revised: 08/17/2020] [Accepted: 09/04/2020] [Indexed: 12/25/2022] Open
Abstract
Background Telomeres shorten as organisms age, placing limits on cell proliferation and serving as a marker of biological aging. Non-esterified fatty acids (NEFAs) are a key mediator of age-related metabolic abnormalities. We aimed to determine if NEFAs are associated with telomere length in community-living older adults. Material and methods We cross-sectionally studied 1648 participants of the Cardiovascular Health Study (CHS) who underwent concomitant telomere length measurement from a sample of 4715 participants who underwent measurement of circulating total fasting NEFAs in stored specimens from their 1992-3 clinic visit. We used linear regression and inverse probability weighting to model telomere length as a function of NEFAs with adjustment for age, gender, race, clinic, BMI, marital status, smoking status, alcohol intake, diabetes status, years of education, hypertension status, prevalent cardiovascular disease, C-reactive protein, total adiponectin, albumin, fetuin-A, fasting insulin, eGFR, total cholesterol, HDL-cholesterol, triglycerides, and general health status. Results Higher NEFAs were significantly associated with shorter telomere length, after adjusting for age, gender, race, and clinic site (β = −0.034; SE = 0.015; P = 0.02). Estimates remained similar in fully adjusted models where each SD of NEFA increment was associated with 0.042 kilobase (kb) pairs shorter telomere length (standard error = 0.016; P = 0.007); for comparison the coefficient for a single year of age in the same model was −0.017. These results were similar in strata of sex, and waist circumference although they tended to be strongest among participants in the youngest tertile of age (β = -0.079; SE = 0.029; P = 0.01). Conclusions In this population-based cohort of community-living elders, we observed a significant inverse association between NEFAs and telomere length. If confirmed, NEFAs may represent a promising target for interventions to slow biological aging.
Shorter telomere lengths have been linked to accelerated aging and disease. Oxidative stress and inflammation drives telomere length shortening. Non-esterified fatty acids induce oxidative stress and inflammation. Higher levels of non-esterified fatty acids were associated with shorter telomeres. Non-esterified fatty acids may be an intervention target to slow biological aging.
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15
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Effect of Antioxidants on the Fibroblast Replicative Lifespan In Vitro. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:6423783. [PMID: 33029282 PMCID: PMC7530501 DOI: 10.1155/2020/6423783] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 09/04/2020] [Accepted: 09/12/2020] [Indexed: 12/20/2022]
Abstract
Replicative senescence is an unalterable growth arrest of primary cells in the culture system. It has been reported that aging in vivo is related to the limited replicative capacity that normal somatic cells show in vitro. If oxidative damage contributes to the lifespan limitation, antioxidants are expected to extend the replicative lifespan of fibroblasts. This article critically reviews the results of experiments devoted to this problem performed within the last decades under conditions of in vitro culture. The results of studied are heterogeneous, some papers showing no effects of antioxidants; most finding limited enhancement of reproductive capacity of fibroblasts, some reporting a significant extension of replicative lifespan (RLS). Both natural and synthetic antioxidants were found to extend the RLS of fibroblasts, either by a direct antioxidant effect or, indirectly, by activation of signaling pathways and activation of proteasomes or hormetic effects. Most significant prolongation of RLS was reported so far for nicotinamide, N-hydroxylamines, carnosine and Methylene Blue. These results may be of importance for the design of skin-protecting cosmetics.
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16
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Chen YF, Dugas TR. Endothelial mitochondrial senescence accelerates cardiovascular disease in antiretroviral-receiving HIV patients. Toxicol Lett 2019; 317:13-23. [PMID: 31562912 DOI: 10.1016/j.toxlet.2019.09.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 09/12/2019] [Accepted: 09/21/2019] [Indexed: 02/06/2023]
Abstract
Combination antiretroviral therapy (cART) has been hugely successful in reducing the mortality associated with human immunodeficiency virus (HIV) infection, resulting in a growing population of people living with HIV (PLWH). Since PLWH now have a longer life expectancy, chronic comorbidities have become the focus of the clinical management of HIV. For example, cardiovascular complications are now one of the most prevalent causes of death in PLWH. Numerous epidemiological studies show that antiretroviral treatment increases cardiovascular disease (CVD) risk and early onset of CVD in PLWH. Nucleoside reverse transcriptase inhibitors (NRTIs) are the backbone of cART, and two NRTIs are typically used in combination with one drug from another drug class, e.g., a fusion inhibitor. NRTIs are known to induce mitochondrial dysfunction, contributing to toxicity in numerous tissues, such as myopathy, lipoatrophy, neuropathy, and nephropathy. In in vitro studies, short-term NRTI treatment induces an endothelial dysfunction with an increased reactive oxygen species (ROS) production; long-term NRTI treatment decreases cell replication capacity, while increasing mtROS production and senescent cell accumulation. These findings suggest that a mitochondrial oxidative stress is involved in the pathogenesis of NRTI-induced endothelial dysfunction and premature senescence. Mitochondrial dysfunction, defined by a compromised mitochondrial quality control via biogenesis and mitophagy, has a causal role in premature endothelial senescence and can potentially initiate early cardiovascular disease (CVD) development in PLWH. In this review, we explore the hypothesis and present literature supporting that long-term NRTI treatment induces vascular dysfunction by interfering with endothelial mitochondrial homeostasis and provoking mitochondrial genomic instability, resulting in premature endothelial senescence.
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Affiliation(s)
- Yi-Fan Chen
- Comparative Biomedical Sciences, Louisiana State University School of Veterinary Medicine, Skip Bertman Drive, Baton Rouge, LA, 70808, United States
| | - Tammy R Dugas
- Comparative Biomedical Sciences, Louisiana State University School of Veterinary Medicine, Skip Bertman Drive, Baton Rouge, LA, 70808, United States.
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17
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de Biase D, Torricelli F, Ragazzi M, Donati B, Kuhn E, Visani M, Acquaviva G, Pession A, Tallini G, Piana S, Ciarrocchi A. Not the same thing: metastatic PTCs have a different background than ATCs. Endocr Connect 2018; 7:1370-1379. [PMID: 30400028 PMCID: PMC6280609 DOI: 10.1530/ec-18-0386] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 10/30/2018] [Indexed: 02/05/2023]
Abstract
Anaplastic thyroid cancer (ATC) is a rare but highly aggressive form of thyroid cancer. By contrast, differentiated papillary thyroid cancer (PTC) only rarely behave aggressively and develop distant metastasis. Whether distantly metastatic PTC (DM-PTC) and ATC share a common genetic background is still to be defined. We used next-generation sequencing (NGS) to explore the genetic background of a cohort of ATC and DM-PTC and a group of well-differentiated PTCs that did not developed distant metastasis as control (ctrl-PTC). A panel of 128 amplicons within 21 thyroid cancer-related genes was analyzed in a set of 151 thyroid cancer samples including 66 ATCs and DM-PTCs. We showed that the ATC/DM-PTC group had an overall mutational load higher than ctrl-PTCs and that ATCs and DM-PTCs are characterized by a different genetic background, with the exception of mutations in the TERT promoter that were overrepresented in both ATCs (61.1%) and DM-PTCs (48.2%) vs non-aggressive ctrl-PTCs (7.6%). In ATCs, TERT promoter mutations were frequently associated with TP53 mutations, while in the DM-PTCs no significant co-occurrence was observed. No significant association of MED12 mutations with aggressiveness of thyroid cancer was observed in our analysis. Finally, correlation analysis showed that increasing number of mutations negatively impact on patient overall survival also within the ATC and DM-PTC group. In conclusions, overall our analysis further highlights the relevance of TERT promoter mutations in driving aggressiveness and provides new pieces of information in the definition of aggressiveness evolution of thyroid cancer lesions.
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Affiliation(s)
- Dario de Biase
- Department of Pharmacy and Biotechnology (Dipartimento di Farmacia e Biotecnologie) – Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna, Bologna, Italy
| | - Federica Torricelli
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale AUSL-IRCCS, Reggio Emilia, Italy
| | - Moira Ragazzi
- Pathology Unit, Azienda Unità Sanitaria Locale AUSL-IRCCS, Reggio Emilia, Italy
| | - Benedetta Donati
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale AUSL-IRCCS, Reggio Emilia, Italy
| | - Elisabetta Kuhn
- Pathology Unit, Azienda Unità Sanitaria Locale AUSL-IRCCS, Reggio Emilia, Italy
| | - Michela Visani
- Department of Medicine (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale) – Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna School of Medicine, Bologna, Italy
| | - Giorgia Acquaviva
- Department of Medicine (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale) – Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna School of Medicine, Bologna, Italy
| | - Annalisa Pession
- Department of Pharmacy and Biotechnology (Dipartimento di Farmacia e Biotecnologie) – Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna, Bologna, Italy
| | - Giovanni Tallini
- Department of Medicine (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale) – Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna School of Medicine, Bologna, Italy
| | - Simonetta Piana
- Pathology Unit, Azienda Unità Sanitaria Locale AUSL-IRCCS, Reggio Emilia, Italy
| | - Alessia Ciarrocchi
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale AUSL-IRCCS, Reggio Emilia, Italy
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18
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Assani G, Xiong Y, Zhou F, Zhou Y. Effect of therapies-mediated modulation of telomere and/or telomerase on cancer cells radiosensitivity. Oncotarget 2018; 9:35008-35025. [PMID: 30405890 PMCID: PMC6201854 DOI: 10.18632/oncotarget.26150] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 07/31/2018] [Indexed: 12/11/2022] Open
Abstract
Cancer is one of the leading causes of death in the world. Many strategies of cancer treatment such as radiotherapy which plays a key role in cancer treatment are developed and used nowadays. However, the side effects post-cancer radiotherapy and cancer radioresistance are two major causes of the limitation of cancer radiotherapy effectiveness in the cancer patients. Moreover, reduction of the limitation of cancer radiotherapy effectiveness by reducing the side effects post-cancer radiotherapy and cancer radioresistance is the aim of several radiotherapy-oncologic teams. Otherwise, Telomere and telomerase are two cells components which play an important role in cancer initiation, cancer progression and cancer therapy resistance such as radiotherapy resistance. For resolving the problems of the limitation of cancer radiotherapy effectiveness especially the cancer radio-resistance problems, the radio-gene-therapy strategy which is the use of gene-therapy via modulation of gene expression combined with radiotherapy was developed and used as a new strategy to treat the patients with cancer. In this review, we summarized the information concerning the implication of telomere and telomerase modulation in cancer radiosensitivity.
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Affiliation(s)
- Ganiou Assani
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Tumor Biology Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yudi Xiong
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Tumor Biology Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Fuxiang Zhou
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Tumor Biology Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yunfeng Zhou
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Tumor Biology Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China
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19
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Mancini A, Xavier-Magalhães A, Woods WS, Nguyen KT, Amen AM, Hayes JL, Fellmann C, Gapinske M, McKinney AM, Hong C, Jones LE, Walsh KM, Bell RJA, Doudna JA, Costa BM, Song JS, Perez-Pinera P, Costello JF. Disruption of the β1L Isoform of GABP Reverses Glioblastoma Replicative Immortality in a TERT Promoter Mutation-Dependent Manner. Cancer Cell 2018; 34:513-528.e8. [PMID: 30205050 PMCID: PMC6135086 DOI: 10.1016/j.ccell.2018.08.003] [Citation(s) in RCA: 98] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Revised: 07/02/2018] [Accepted: 08/03/2018] [Indexed: 12/27/2022]
Abstract
TERT promoter mutations reactivate telomerase, allowing for indefinite telomere maintenance and enabling cellular immortalization. These mutations specifically recruit the multimeric ETS factor GABP, which can form two functionally independent transcription factor species: a dimer or a tetramer. We show that genetic disruption of GABPβ1L (β1L), a tetramer-forming isoform of GABP that is dispensable for normal development, results in TERT silencing in a TERT promoter mutation-dependent manner. Reducing TERT expression by disrupting β1L culminates in telomere loss and cell death exclusively in TERT promoter mutant cells. Orthotopic xenografting of β1L-reduced, TERT promoter mutant glioblastoma cells rendered lower tumor burden and longer overall survival in mice. These results highlight the critical role of GABPβ1L in enabling immortality in TERT promoter mutant glioblastoma.
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Affiliation(s)
- Andrew Mancini
- Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA
| | - Ana Xavier-Magalhães
- Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, 4710-057 Braga, Portugal
| | - Wendy S Woods
- Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Kien-Thiet Nguyen
- Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA
| | - Alexandra M Amen
- Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA
| | - Josie L Hayes
- Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA
| | - Christof Fellmann
- Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA
| | - Michael Gapinske
- Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Andrew M McKinney
- Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA
| | - Chibo Hong
- Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA
| | - Lindsey E Jones
- Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA
| | - Kyle M Walsh
- Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA
| | - Robert J A Bell
- Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA
| | - Jennifer A Doudna
- Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA; Department of Chemistry, University of California, Berkeley, CA 94720, USA; Innovative Genomics Institute, University of California, Berkeley, CA 94720, USA; MBIB Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Howard Hughes Medical Institute (HHMI), Berkeley, CA 94720, USA
| | - Bruno M Costa
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, 4710-057 Braga, Portugal
| | - Jun S Song
- Department of Physics, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA; Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Pablo Perez-Pinera
- Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA; Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Joseph F Costello
- Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA.
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20
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Tricola GM, Simons MJP, Atema E, Boughton RK, Brown JL, Dearborn DC, Divoky G, Eimes JA, Huntington CE, Kitaysky AS, Juola FA, Lank DB, Litwa HP, Mulder EGA, Nisbet ICT, Okanoya K, Safran RJ, Schoech SJ, Schreiber EA, Thompson PM, Verhulst S, Wheelwright NT, Winkler DW, Young R, Vleck CM, Haussmann MF. The rate of telomere loss is related to maximum lifespan in birds. Philos Trans R Soc Lond B Biol Sci 2018; 373:20160445. [PMID: 29335369 PMCID: PMC5784065 DOI: 10.1098/rstb.2016.0445] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/02/2017] [Indexed: 02/06/2023] Open
Abstract
Telomeres are highly conserved regions of DNA that protect the ends of linear chromosomes. The loss of telomeres can signal an irreversible change to a cell's state, including cellular senescence. Senescent cells no longer divide and can damage nearby healthy cells, thus potentially placing them at the crossroads of cancer and ageing. While the epidemiology, cellular and molecular biology of telomeres are well studied, a newer field exploring telomere biology in the context of ecology and evolution is just emerging. With work to date focusing on how telomere shortening relates to individual mortality, less is known about how telomeres relate to ageing rates across species. Here, we investigated telomere length in cross-sectional samples from 19 bird species to determine how rates of telomere loss relate to interspecific variation in maximum lifespan. We found that bird species with longer lifespans lose fewer telomeric repeats each year compared with species with shorter lifespans. In addition, phylogenetic analysis revealed that the rate of telomere loss is evolutionarily conserved within bird families. This suggests that the physiological causes of telomere shortening, or the ability to maintain telomeres, are features that may be responsible for, or co-evolved with, different lifespans observed across species.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.
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Affiliation(s)
- Gianna M Tricola
- Department of Biology, Bucknell University, Lewisburg, PA 17837, USA
| | - Mirre J P Simons
- Department of Animal and Plant Sciences, The University of Sheffield, Sheffield S10 2TN, UK
| | - Els Atema
- Groningen Institute for Evolutionary Life Sciences, University of Groningen, 9700AB Groningen, Netherlands
| | - Raoul K Boughton
- Department of Biology, University of Memphis, Memphis, TN 38152, USA
| | - J L Brown
- Department of Biological Sciences, University of Albany, Albany, NY 12222, USA
| | | | - G Divoky
- Friends of Cooper Island, Seattle, WA 98112, USA
| | - John A Eimes
- Department of Biological Sciences, University College, Sungkyunkwan University, Suwon 16419, Korea
| | | | | | - Frans A Juola
- Department of Biology, Bucknell University, Lewisburg, PA 17837, USA
| | - David B Lank
- Department of Biological Sciences, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6
| | - Hannah P Litwa
- Department of Biology, Bucknell University, Lewisburg, PA 17837, USA
| | - Ellis G A Mulder
- Groningen Institute for Evolutionary Life Sciences, University of Groningen, 9700AB Groningen, Netherlands
| | | | - Kazuo Okanoya
- Department of Life Sciences, The University of Tokyo, Tokyo 113-8654, Japan
| | - Rebecca J Safran
- Department of Ecology and Evolutionary Biology, University of Colorado, Boulder, CO 80309, USA
| | - Stephan J Schoech
- Department of Biology, University of Memphis, Memphis, TN 38152, USA
| | - Elizabeth A Schreiber
- National Museum of Natural History, Smithsonian Institution, Washington, DC 20560, USA
| | - Paul M Thompson
- Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, AB24 3FX, UK
| | - Simon Verhulst
- Groningen Institute for Evolutionary Life Sciences, University of Groningen, 9700AB Groningen, Netherlands
| | | | - David W Winkler
- Department of Ecology and Evolutionary Biology, Cornell University, Ithaca, NY 14853, USA
| | - Rebecca Young
- Institute of Arctic Biology, University of Alaska, Fairbanks, AK 99775, USA
| | - Carol M Vleck
- Department of Ecology, Evolution, and Organismal Biology, Iowa State University, Ames, IA 50011, USA
| | - Mark F Haussmann
- Department of Biology, Bucknell University, Lewisburg, PA 17837, USA
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21
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Abstract
Many risk factors have been firmly established for pancreatic cancer (PC), but the molecular processes by which known risk factors influence susceptibility to PC are not clear. There has been a recent upsurge of interest in the role of telomere length (TL), the protective DNA sequence repeats at chromosome ends, in pancreatic carcinogenesis. Given this heightened interest, we performed an in-depth, focused, and up-to-date review of the epidemiological evidence linking leukocyte TL (LTL) with PC risk. We searched MEDLINE, Embase, and the Cochrane Library databases for all published studies on LTL and PC risk, up to May 2017. Five studies were identified for review: four nested case-control studies and one retrospective case-control study. Two studies found opposite associations between LTL and PC risk; one found a dose-response positive association and the other found a dose-response inverse association. Two studies also found a “U-shaped” association, while another reported a weak nonlinear relationship. We offer potential reasons for the conflicting findings including variation in study design, biospecimen characteristics, and differences in inter-laboratory measurements of TL. Future studies should carefully control for risk factors of PC that are associated also with telomere attrition, and investigate the role of genetic variation in TL maintenance.
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Affiliation(s)
- Samuel O. Antwi
- Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL
| | - Gloria M. Petersen
- Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN
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Association of leukocyte telomere length and the risk of age-related hearing impairment in Chinese Hans. Sci Rep 2017; 7:10106. [PMID: 28860610 PMCID: PMC5578975 DOI: 10.1038/s41598-017-10680-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 08/14/2017] [Indexed: 12/19/2022] Open
Abstract
Age-related hearing loss (ARHI) is the most common sensory disorder in the elderly. Although telomere attrition has been shown as a determinant in the pathobiology of various age-related diseases, it remains unknown whether telomere length is associated with ARHI. We hypothesized that decreased leukocyte telomere length (LTL) increased the risk of ARHI. Thus, we measured LTL of 666 ARHI and 43 controls by an established quantitative PCR technique. Four audiogram shape subtypes of ARHI, including “flat shape (FL)”, “2–4 kHz abrupt loss (AL) shape”, “8 kHz dip (8D) shape” and “sloping shape (SL)” could be identified among the cases using K-means cluster analysis. Longer LTL was associated with the reduced incidence of ARHI (adjusted OR = 0.550, 95% CI: 0.420–0.721, P < 0.0001 for all the ARHI; 0.498, 0.318–0.780, P = 0.0023 for FL subgroup; 0.428, 0.292–0.628, P < 0.0001 for AL subgroup; 0.552, 0.399–0.764, P = 0.0003 for mSL subgroup). Subjects in the highest tertile of LTL were at less risk for ARHI than those in the lowest and middle tertiles (OR for ARHI: 0.327, 95% CI 0.170–0.629, P = 0.0008). There was a descending trend of LTL as the degree of pure tone threshold average (PTA) aggravated. These results suggest that telomere attrition may be involved in the progression of ARHI.
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Treating Cancer by Targeting Telomeres and Telomerase. Antioxidants (Basel) 2017; 6:antiox6010015. [PMID: 28218725 PMCID: PMC5384178 DOI: 10.3390/antiox6010015] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 02/15/2017] [Accepted: 02/16/2017] [Indexed: 12/22/2022] Open
Abstract
Telomerase is expressed in more than 85% of cancer cells. Tumor cells with metastatic potential may have a high telomerase activity, allowing cells to escape from the inhibition of cell proliferation due to shortened telomeres. Human telomerase primarily consists of two main components: hTERT, a catalytic subunit, and hTR, an RNA template whose sequence is complimentary to the telomeric 5′-dTTAGGG-3′ repeat. In humans, telomerase activity is typically restricted to renewing tissues, such as germ cells and stem cells, and is generally absent in normal cells. While hTR is constitutively expressed in most tissue types, hTERT expression levels are low enough that telomere length cannot be maintained, which sets a proliferative lifespan on normal cells. However, in the majority of cancers, telomerase maintains stable telomere length, thereby conferring cell immortality. Levels of hTERT mRNA are directly related to telomerase activity, thereby making it a more suitable therapeutic target than hTR. Recent data suggests that stabilization of telomeric G-quadruplexes may act to indirectly inhibit telomerase action by blocking hTR binding. Telomeric DNA has the propensity to spontaneously form intramolecular G-quadruplexes, four-stranded DNA secondary structures that are stabilized by the stacking of guanine residues in a planar arrangement. The functional roles of telomeric G-quadruplexes are not completely understood, but recent evidence suggests that they can stall the replication fork during DNA synthesis and inhibit telomere replication by preventing telomerase and related proteins from binding to the telomere. Long-term treatment with G-quadruplex stabilizers induces a gradual reduction in the length of the G-rich 3’ end of the telomere without a reduction of the total telomere length, suggesting that telomerase activity is inhibited. However, inhibition of telomerase, either directly or indirectly, has shown only moderate success in cancer patients. Another promising approach of targeting the telomere is the use of guanine-rich oligonucleotides (GROs) homologous to the 3’ telomere overhang sequence (T-oligos). T-oligos, particularly a specific 11-base oligonucleotide (5’-dGTTAGGGTTAG-3’) called T11, have been shown to induce DNA damage responses (DDRs) such as senescence, apoptosis, and cell cycle arrest in numerous cancer cell types with minimal or no cytostatic effects in normal, non-transformed cells. As a result, T-oligos and other GROs are being investigated as prospective anticancer therapeutics. Interestingly, the DDRs induced by T-oligos in cancer cells are similar to the effects seen after progressive telomere degradation in normal cells. The loss of telomeres is an important tumor suppressor mechanism that is commonly absent in transformed malignant cells, and hence, T-oligos have garnered significant interest as a novel strategy to combat cancer. However, little is known about their mechanism of action. In this review, we discuss the current understanding of how T-oligos exert their antiproliferative effects in cancer cells and their role in inhibition of telomerase. We also discuss the current understanding of telomerase in cancer and various therapeutic targets related to the telomeres and telomerase.
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Cortese FAB, Santostasi G. Whole-Body Induced Cell Turnover: A Proposed Intervention for Age-Related Damage and Associated Pathology. Rejuvenation Res 2016; 19:322-36. [PMID: 26649945 DOI: 10.1089/rej.2015.1763] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
In both biomedicine in general and biomedical gerontology in particular, cell replacement therapy is traditionally proposed as an intervention for cell loss. This article presents a proposed intervention-whole-body induced cell turnover (WICT)-for use in biomedical gerontology that combines cell replacement therapy with a second therapeutic component (targeted cell ablation) so as to broaden the therapeutic utility of cell therapies and increase the categories of age-related damage that are amenable to cell-based interventions. In particular, WICT may allow cell therapies to serve as an intervention for accumulated cellular and intracellular damage, such as telomere depletion, genomic DNA and mitochondrial DNA damage and mutations, replicative senescence, functionally deleterious age-related changes in gene expression, accumulated cellular and intracellular aggregates, and functionally deleterious posttranslationally modified gene products. WICT consists of the gradual ablation and subsequent replacement of a patient's entire set of constituent cells gradually over the course of their adult life span through the quantitative and qualitative coordination of targeted cell ablation with exogenous cell administration. The aim is to remove age-associated cellular and intracellular damage present in the patient's endogenous cells. In this study, we outline the underlying techniques and technologies by which WICT can be mediated, describe the mechanisms by which it can serve to negate or prevent age-related cellular and intracellular damage, explicate the unique therapeutic components and utilities that distinguish it as a distinct type of cell-based intervention for use in biomedical gerontology, and address potential complications associated with the therapy.
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Affiliation(s)
| | - Giovanni Santostasi
- 2 Department of Neurology, Feinberg School of Medicine, Northwestern University , Chicago, Illinois
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Marthandan S, Priebe S, Hemmerich P, Klement K, Diekmann S. Long-term quiescent fibroblast cells transit into senescence. PLoS One 2014; 9:e115597. [PMID: 25531649 PMCID: PMC4274099 DOI: 10.1371/journal.pone.0115597] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Accepted: 11/28/2014] [Indexed: 12/16/2022] Open
Abstract
Cellular senescence is described to be a consequence of telomere erosion during the replicative life span of primary human cells. Quiescence should therefore not contribute to cellular aging but rather extend lifespan. Here we tested this hypothesis and demonstrate that cultured long-term quiescent human fibroblasts transit into senescence due to similar cellular mechanisms with similar dynamics and with a similar maximum life span as proliferating controls, even under physiological oxygen conditions. Both, long-term quiescent and senescent fibroblasts almost completely fail to undergo apoptosis. The transition of long-term quiescent fibroblasts into senescence is also independent of HES1 which protects short-term quiescent cells from becoming senescent. Most significantly, DNA damage accumulates during senescence as well as during long-term quiescence at physiological oxygen levels. We suggest that telomere-independent, potentially maintenance driven gradual induction of cellular senescence during quiescence is a counterbalance to tumor development.
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Affiliation(s)
- Shiva Marthandan
- Leibniz-Institute for Age Research- Fritz Lipmann Institute, JenAge (Jena Centre for Systems Biology of Aging), Beutenbergstrasse 11, Jena, Germany
| | - Steffen Priebe
- Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institute e.V. (HKI), Jena, Germany
| | - Peter Hemmerich
- Leibniz-Institute for Age Research- Fritz Lipmann Institute, JenAge (Jena Centre for Systems Biology of Aging), Beutenbergstrasse 11, Jena, Germany
| | - Karolin Klement
- Leibniz-Institute for Age Research- Fritz Lipmann Institute, JenAge (Jena Centre for Systems Biology of Aging), Beutenbergstrasse 11, Jena, Germany
| | - Stephan Diekmann
- Leibniz-Institute for Age Research- Fritz Lipmann Institute, JenAge (Jena Centre for Systems Biology of Aging), Beutenbergstrasse 11, Jena, Germany
- * E-mail:
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26
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Siegl C, Prusty BK, Karunakaran K, Wischhusen J, Rudel T. Tumor suppressor p53 alters host cell metabolism to limit Chlamydia trachomatis infection. Cell Rep 2014; 9:918-29. [PMID: 25437549 DOI: 10.1016/j.celrep.2014.10.004] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Revised: 07/21/2014] [Accepted: 09/30/2014] [Indexed: 11/30/2022] Open
Abstract
Obligate intracellular bacteria depend entirely on nutrients from the host cell for their reproduction. Here, we show that obligate intracellular Chlamydia downregulate the central tumor suppressor p53 in human cells. This reduction of p53 levels is mediated by the PI3K-Akt signaling pathway, activation of HDM2, and subsequent proteasomal degradation of p53. The stabilization of p53 in human cells severely impaired chlamydial development and caused the loss of infectious particle formation. DNA-damage-induced p53 interfered with chlamydial development through downregulation of the pentose phosphate pathway (PPP). Increased expression of the PPP key enzyme glucose-6-phosphate dehydrogenase rescued the inhibition of chlamydial growth induced by DNA damage or stabilized p53. Thus, downregulation of p53 is a key event in the chlamydial life cycle that reprograms the host cell to create a metabolic environment supportive of chlamydial growth.
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Affiliation(s)
- Christine Siegl
- Department of Microbiology, University of Würzburg Biocenter, Am Hubland, 97074 Würzburg, Germany
| | - Bhupesh K Prusty
- Department of Microbiology, University of Würzburg Biocenter, Am Hubland, 97074 Würzburg, Germany
| | - Karthika Karunakaran
- Department of Microbiology, University of Würzburg Biocenter, Am Hubland, 97074 Würzburg, Germany
| | - Jörg Wischhusen
- Frauenklinik, University Clinic Würzburg, Josef-Schneider-Str. 4, 97080 Würzburg, Germany
| | - Thomas Rudel
- Department of Microbiology, University of Würzburg Biocenter, Am Hubland, 97074 Würzburg, Germany.
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Senescent cells: SASPected drivers of age-related pathologies. Biogerontology 2014; 15:627-42. [PMID: 25217383 DOI: 10.1007/s10522-014-9529-9] [Citation(s) in RCA: 147] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Accepted: 09/01/2014] [Indexed: 12/19/2022]
Abstract
The progression of physiological ageing is driven by intracellular aberrations including telomere attrition, genomic instability, epigenetic alterations and loss of proteostasis. These in turn damage cells and compromise their functionality. Cellular senescence, a stable irreversible cell-cycle arrest, is elicited in damaged cells and prevents their propagation in the organism. Under normal conditions, senescent cells recruit the immune system which facilitates their removal from tissues. Nevertheless, during ageing, tissue-residing senescent cells tend to accumulate, and might negatively impact their microenvironment via profound secretory phenotype with pro-inflammatory characteristics, termed senescence-associated secretory phenotype (SASP). Indeed, senescent cells are mostly abundant at sites of age-related pathologies, including degenerative disorders and malignancies. Interestingly, studies on progeroid mice indicate that selective elimination of senescent cells can delay age-related deterioration. This suggests that chronic inflammation induced by senescent cells might be a main driver of these pathologies. Importantly, senescent cells accumulate as a result of deficient immune surveillance, and their removal is increased upon the use of immune stimulatory agents. Insights into mechanisms of senescence surveillance could be combined with current approaches for cancer immunotherapy to propose new preventive and therapeutic strategies for age-related diseases.
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Mania A, Mantzouratou A, Delhanty JD, Baio G, Serhal P, Sengupta SB. Telomere length in human blastocysts. Reprod Biomed Online 2014; 28:624-37. [DOI: 10.1016/j.rbmo.2013.12.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2013] [Revised: 12/10/2013] [Accepted: 12/18/2013] [Indexed: 11/27/2022]
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Chen W, Qin L, Wang S, Li M, Shi D, Tian Y, Wang J, Fu L, Li Z, Guo W, Yu W, Yuan Y, Kang T, Huang W, Deng W. CPSF4 activates telomerase reverse transcriptase and predicts poor prognosis in human lung adenocarcinomas. Mol Oncol 2014; 8:704-16. [PMID: 24618080 DOI: 10.1016/j.molonc.2014.02.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Revised: 01/06/2014] [Accepted: 02/05/2014] [Indexed: 01/01/2023] Open
Abstract
The elevated expression and activation of human telomerase reverse transcriptase (hTERT) is associated with the unlimited proliferation of cancer cells. However, the excise mechanism of hTERT regulation during carcinogenesis is not well understood. In this study, we discovered cleavage and polyadenylation specific factor 4 (CPSF4) as a novel tumor-specific hTERT promoter-regulating protein in lung cancer cells and identified the roles of CPSF4 in regulating lung hTERT and lung cancer growth. The ectopic overexpression of CPSF4 upregulated the hTERT promoter-driven report gene expression and activated the endogenous hTERT mRNA and protein expression and the telomerase activity in lung cancer cells and normal lung cells. In contrast, the knockdown of CPSF4 by siRNA had the opposite effects. CPSF4 knockdown also significantly inhibited tumor cell growth in lung cancer cells in vitro and in a xenograft mouse model in vivo, and this inhibitory effect was partially mediated by decreasing the expression of hTERT. High expression of both CPSF4 and hTERT proteins were detected in lung adenocarcinoma cells by comparison with the normal lung cells. Tissue microarray immunohistochemical analysis of lung adenocarcinomas also revealed a strong positive correlation between the expression of CPSF4 and hTERT proteins. Moreover, Kaplan-Meier analysis showed that patients with high levels of CPSF4 and hTERT expression had a significantly shorter overall survival than those with low CPSF4 and hTERT expression levels. Collectively, these results demonstrate that CPSF4 plays a critical role in the regulation of hTERT expression and lung tumorigenesis and may be a new prognosis factor in lung adenocarcinomas.
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Affiliation(s)
- Wangbing Chen
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Lijun Qin
- Department of Pediatrics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Shusen Wang
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
| | - Mei Li
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Dingbo Shi
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Yun Tian
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Jingshu Wang
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Lingyi Fu
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Zhenglin Li
- Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China
| | - Wei Guo
- Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China
| | - Wendan Yu
- Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China
| | - Yuhui Yuan
- Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China
| | - Tiebang Kang
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Wenlin Huang
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China; State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China.
| | - Wuguo Deng
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China; State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China.
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Pitman RT, Wojdyla L, Puri N. Mechanism of DNA damage responses induced by exposure to an oligonucleotide homologous to the telomere overhang in melanoma. Oncotarget 2014; 4:761-71. [PMID: 23800953 PMCID: PMC3742836 DOI: 10.18632/oncotarget.1047] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
T-oligo, an 11-base oligonucleotide homologous to the 3'-telomeric overhang, is a novel, potent therapeutic modality in melanoma and multiple other tumor types. T-oligo is proposed to function in a manner similar to experimental disruption of the telomere overhang and induces DNA damage responses including apoptosis, differentiation and senescence. However, important components involved in T-oligo induced responses are not defined, particularly the role of p53, TRF1 and TRF2 in mediating the T-oligo induced responses. In MU, PM-WK, and MM-MC melanoma cells, exposure to T-oligo upregulates p53 expression and phosphorylation, resulting in cellular differentiation and activation of a caspase-mediated apoptotic cascade. However, siRNA-mediated knockdown of p53 completely blocks T-oligo induced differentiation and significantly decreases apoptosis, suggesting that p53 is an important mediator of T-oligo induced responses. In addition, we characterized the roles of telomere binding proteins, TRF1, TRF2, and tankyrase-1, in T-oligo induced damage responses. We demonstrate that tankyrase-1 activity is required for initiation of T-oligo induced damage responses including p53 phosphorylation and reduction of cellular proliferation. These results highlight TRF1, TRF2, tankyrase-1 and p53 as important elements in T-oligo mediated responses and suggest new avenues for research into T-oligo's mechanism of action.
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Affiliation(s)
- Ryan T Pitman
- Department of Biomedical Sciences, University of Illinois College of Medicine, Rockford, Illinois, USA
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Fukuda R, Suico MA, Koyama K, Omachi K, Kai Y, Matsuyama S, Mitsutake K, Taura M, Morino-Koga S, Shuto T, Kai H. Mild electrical stimulation at 0.1-ms pulse width induces p53 protein phosphorylation and G2 arrest in human epithelial cells. J Biol Chem 2013; 288:16117-26. [PMID: 23599430 DOI: 10.1074/jbc.m112.442442] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Exogenous low-intensity electrical stimulation has been used for treatment of various intractable diseases despite the dearth of information on the molecular underpinnings of its effects. Our work and that of others have demonstrated that applied electrical stimulation at physiological strength or mild electrical stimulation (MES) activates the PI3K-Akt pathway, but whether MES activates other molecules remains unknown. Considering that MES is a form of physiological stress, we hypothesized that it can activate the tumor suppressor p53, which is a key modulator of the cell cycle and apoptosis in response to cell stresses. The potential response of p53 to an applied electrical current of low intensity has not been investigated. Here, we show that p53 was transiently phosphorylated at Ser-15 in epithelial cells treated with an imperceptible voltage (1 V/cm) and a 0.1-ms pulse width. MES-induced p53 phosphorylation was inhibited by pretreatment with a p38 MAPK inhibitor and transfection of dominant-negative mutants of p38, MKK3b, and MKK6b, implying the involvement of the p38 MAPK signaling pathway. Furthermore, MES treatment enhanced p53 transcriptional function and increased the expression of p53 target genes p21, BAX, PUMA, NOXA, and IRF9. Importantly, MES treatment triggered G2 cell cycle arrest, but not cell apoptosis. MES treatment had no effect on the cell cycle in HCT116 p53(-/-) cells, suggesting a dependence on p53. These findings identify some molecular targets of electrical stimulation and incorporate the p38-p53 signaling pathway among the transduction pathways that MES affects.
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Affiliation(s)
- Ryosuke Fukuda
- Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan
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Sanders JL, Newman AB. Telomere length in epidemiology: a biomarker of aging, age-related disease, both, or neither? Epidemiol Rev 2013; 35:112-31. [PMID: 23302541 DOI: 10.1093/epirev/mxs008] [Citation(s) in RCA: 396] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2012] [Indexed: 01/03/2023] Open
Abstract
Telomeres are nucleoprotein caps flanking DNA. They are shortened by cell division and oxidative stress and are lengthened by the enzyme telomerase and DNA exchange during mitosis. Short telomeres induce cellular senescence. As an indicator of oxidative stress and senescence (2 processes thought to be fundamental to aging), telomere length is hypothesized to be a biomarker of aging. This hypothesis has been tested for more than a decade with epidemiologic study methods. In cross-sectional studies, researchers have investigated whether leukocyte telomere length (LTL) is associated with demographic, behavioral, and health variables. In prospective studies, baseline LTL has been used to predict mortality and occasionally other adverse health outcomes. Conflicting data have generated heated debate about the value of LTL as a biomarker of overall aging. In this review, we address the epidemiologic data on LTL and demonstrate that shorter LTL is associated with older age, male gender, Caucasian race, and possibly atherosclerosis; associations with other markers of health are equivocal. We discuss the reasons for discrepancy across studies, including a detailed review of methods for measuring telomere length as they apply to epidemiology. Finally, we conclude with questions about LTL as a biomarker of aging and how epidemiology can be used to answer these questions.
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Sfikas A, Batsi C, Tselikou E, Vartholomatos G, Monokrousos N, Pappas P, Christoforidis S, Tzavaras T, Kanavaros P, Gorgoulis VG, Marcu KB, Kolettas E. The canonical NF-κB pathway differentially protects normal and human tumor cells from ROS-induced DNA damage. Cell Signal 2012; 24:2007-23. [PMID: 22750558 DOI: 10.1016/j.cellsig.2012.06.010] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2012] [Revised: 06/06/2012] [Accepted: 06/16/2012] [Indexed: 10/28/2022]
Abstract
DNA damage responses (DDR) invoke senescence or apoptosis depending on stimulus intensity and the degree of activation of the p53-p21(Cip1/Waf1) axis; but the functional impact of NF-κB signaling on these different outcomes in normal vs. human cancer cells remains poorly understood. We investigated the NF-κB-dependent effects and mechanism underlying reactive oxygen species (ROS)-mediated DDR outcomes of normal human lung fibroblasts (HDFs) and A549 human lung cancer epithelial cells. To activate DDR, ROS accumulation was induced by different doses of H(2)O(2). The effect of ROS induction caused a G2 or G2-M phase cell cycle arrest of both human cell types. However, ROS-mediated DDR eventually culminated in different end points with HDFs undergoing premature senescence and A549 cancer cells succumbing to apoptosis. NF-κB p65/RelA nuclear translocation and Ser536 phosphorylation were induced in response to H(2)O(2)-mediated ROS accumulation. Importantly, blocking the activities of canonical NF-κB subunits with an IκBα super-repressor or suppressing canonical NF-κB signaling by IKKβ knock-down accelerated HDF premature senescence by up-regulating the p53-p21(Cip1/Waf1) axis; but inhibiting the canonical NF-κB pathway exacerbated H(2)O(2)-induced A549 cell apoptosis. HDF premature aging occurred in conjunction with γ-H2AX chromatin deposition, senescence-associated heterochromatic foci and beta-galactosidase staining. p53 knock-down abrogated H(2)O(2)-induced premature senescence of vector control- and IκBαSR-expressing HDFs functionally linking canonical NF-κB-dependent control of p53 levels to ROS-induced HDF senescence. We conclude that IKKβ-driven canonical NF-κB signaling has different functional roles for the outcome of ROS responses in the contexts of normal vs. human tumor cells by respectively protecting them against DDR-dependent premature senescence and apoptosis.
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Affiliation(s)
- Alexandros Sfikas
- Cell and Molecular Physiology Unit, Laboratory of Physiology, School of Medicine, University of Ioannina, 45110 Ioannina, Greece
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A zebrafish model of dyskeratosis congenita reveals hematopoietic stem cell formation failure resulting from ribosomal protein-mediated p53 stabilization. Blood 2011; 118:5458-65. [PMID: 21921046 DOI: 10.1182/blood-2011-04-351460] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Dyskeratosis congenita (DC) is a bone marrow failure disorder characterized by shortened telomeres, defective stem cell maintenance, and highly heterogeneous phenotypes affecting predominantly tissues that require high rates of turnover. Here we present a mutant zebrafish line with decreased expression of nop10, one of the known H/ACA RNP complex genes with mutations linked to DC. We demonstrate that this nop10 loss results in 18S rRNA processing defects and collapse of the small ribosomal subunit, coupled to stabilization of the p53 tumor suppressor protein through small ribosomal proteins binding to Mdm2. These mutants also display a hematopoietic stem cell deficiency that is reversible on loss of p53 function. However, we detect no changes in telomere length in nop10 mutants. Our data support a model of DC whereupon in early development mutations involved in the H/ACA complex contribute to bone marrow failure through p53 deregulation and loss of initial stem cell numbers while their role in telomere maintenance does not contribute to DC until later in life.
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Dekker P, de Lange MJ, Dirks RW, van Heemst D, Tanke HJ, Westendorp RGJ, Maier AB. Relation between maximum replicative capacity and oxidative stress-induced responses in human skin fibroblasts in vitro. J Gerontol A Biol Sci Med Sci 2010; 66:45-50. [PMID: 20937674 DOI: 10.1093/gerona/glq159] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Cellular senescence, an important factor in ageing phenotypes, can be induced by replicative exhaustion or by stress. We investigated the relation between maximum replicative capacity, telomere length, stress-induced cellular senescence, and apoptosis/cell death in human primary fibroblast strains obtained from nonagenarians of the Leiden 85-plus Study. Fibroblast strains were cultured until replicative senescence and stressed with rotenone at low passage. Telomere length, senescence-associated-β-galactosidase activity, sub-G1 content, and Annexin-V/PI positivity were measured in nonstressed and stressed conditions. Fibroblast strains with a higher replicative capacity had longer telomeres (p = .054). In nonstressed conditions, replicative capacity was not associated with β-gal activity (p = .07) and negatively with sub-G1 (p = .008). In rotenone-stressed conditions, replicative capacity was negatively associated with β-gal activity (p = .034) and positively with sub-G1 (p = .07). Summarizing, fibroblast strains with a higher maximum replicative capacity have longer telomeres, are less prone to go into stress-induced cellular senescence, and more prone to die after stress.
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Affiliation(s)
- Pim Dekker
- Department of Gerontology and Geriatrics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
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Zielke S, Bodnar A. Telomeres and telomerase activity in scleractinian corals and Symbiodinium spp. THE BIOLOGICAL BULLETIN 2010; 218:113-121. [PMID: 20413788 DOI: 10.1086/bblv218n2p113] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2023]
Abstract
Telomeres are the repetitive sequences of DNA and associated proteins that cap the ends of eukaryotic chromosomes and play an essential role in maintaining chromosome stability. Compromised telomeres can lead to cell cycle arrest, senescence, apoptosis, or genetic instability, whereas maintenance of telomeres can endow cells with the capacity for indefinite self-renewal. Telomere integrity is maintained in most cells by the activity of telomerase, a ribonucleoprotein that can catalyze the addition of repeat sequences onto chromosome ends. Using the telomeric repeat amplification protocol (TRAP) assay, we detected telomerase activity in host nuclear extracts prepared from two scleractinian corals, Madracis auretenra and Madracis decactis, and also in cultured Symbiodinium, the symbiotic algae that live within corals. Sequencing the TRAP reaction products indicated that the telomeric DNA repeat sequence was TTAGGG for coral and TTTAGGG for Symbiodinium. Using this sequence information, we estimated telomere lengths by terminal restriction fragment (TRF) analysis to be greater than 19 kb for several species of coral and their associated Symbiodinium. Maintenance of coral telomeres by telomerase activity may be a mechanism that confers continuous growth and reproductive plasticity to these long-lived organisms.
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Affiliation(s)
- Sandra Zielke
- Bermuda Institute of Ocean Sciences, Ferry Reach, St. George's, Bermuda
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Chen W, Gardner JP, Kimura M, Brimacombe M, Cao X, Srinivasan SR, Berenson GS, Aviv A. Leukocyte telomere length is associated with HDL cholesterol levels: The Bogalusa heart study. Atherosclerosis 2009; 205:620-5. [PMID: 19230891 DOI: 10.1016/j.atherosclerosis.2009.01.021] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2008] [Revised: 01/14/2009] [Accepted: 01/14/2009] [Indexed: 10/21/2022]
Abstract
OBJECTIVE This study examined the relationships of high-density lipoprotein cholesterol (HDL-C) with LTL and the rate of its shortening. BACKGROUND Diminished levels of HDL-C are associated with an increased risk for atherosclerosis. Shortened leukocyte telomere length (LTL) also entails an increased atherosclerotic risk. METHODS We studied 472 Whites and 190 African Americans (AfAs) enrolled in the Bogalusa Heart Study. Subjects were examined serially 3-13 times for HDL-C over an average period of 27.8 years from childhood through young adulthood. LTL was measured twice during adulthood at a mean age of 31.5 years (baseline exam) and 37.8 years (follow-up exam). HDL-C trajectories with age were constructed and the area under the curve (AUC) was used as a measure of cumulative HDL-C levels. RESULTS Multivariate regression analyses showed that LTL was positively associated with HDL-C in childhood (regression coefficient (bp per mg/dL) beta=3.1, p=0.024), adulthood (beta=4.4, p=0.058) and AUC from childhood to adulthood (beta=12.2, p=0.0004) in the combined sample of AfAs and Whites. The association between LTL and HDL-C AUC was stronger in females (beta=18.5, p<0.001) than in males (beta=2.9, p=0.590) (difference in slopes p=0.037). A slower rate of LTL shortening per year was associated with higher HDL-C AUC in the total sample (p=0.033), adjusting for baseline LTL. CONCLUSIONS As HDL-C exerts anti-oxidant and anti-inflammatory effects and LTL registers the accruing burden of oxidative stress and inflammation, the association between HDL-C and LTL might be explained by the lifelong status of oxidative stress and inflammation.
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Affiliation(s)
- Wei Chen
- Tulane Center for Cardiovascular Health, Tulane University Health Sciences, New Orleans, LA 70112, United States.
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Hunt SC, Chen W, Gardner JP, Kimura M, Srinivasan SR, Eckfeldt JH, Berenson GS, Aviv A. Leukocyte telomeres are longer in African Americans than in whites: the National Heart, Lung, and Blood Institute Family Heart Study and the Bogalusa Heart Study. Aging Cell 2008; 7:451-8. [PMID: 18462274 PMCID: PMC2810865 DOI: 10.1111/j.1474-9726.2008.00397.x] [Citation(s) in RCA: 239] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/01/2008] [Indexed: 12/14/2022] Open
Abstract
Leukocyte telomere length (LTL) is ostensibly a bio-indicator of human aging. Here we report that African Americans have longer LTL than whites. We studied cross-sectionally 2453 individuals from the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study (age = 30-93 years) and the Bogalusa Heart Study (age = 19-37 years), comprising 1742 whites and 711 African Americans. We measured LTL by Southern blots of the terminal restriction fragments length. In 234 participants, telomere repeats were also measured by quantitative polymerase chain reaction (qPCR). Adjusted for age and body mass index (BMI), the respective leukocyte telomere lengths (mean +/- SEM) were considerably longer in African Americans than in whites both in the Family Heart Study (7.004 +/- 0.033 kb vs. 6.735 +/- 0.024 kb, p < 0.0001) and the Bogalusa Heart Study (7.923 +/- 0.063 kb vs. 7.296 +/- 0.039 kb, p < 0.0001). We confirmed the racial effect on LTL by qPCR (3.038 +/- 0.565 T/S units for African Americans vs. 2.714 +/- 0.487 T/S units for whites, p < 0.001). Cross-sectionally, sex- and BMI-adjusted LTL became shorter with age (range 19-93 years) at a steeper slope in African Americans than in whites (0.029 kb year(-1) vs. 0.020 kb year(-1), respectively, p = 0.0001). We suggest that racial difference in LTL arises from a host of interacting biological factors, including replication rates of hematopoietic stem cells.
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Affiliation(s)
- Steven C Hunt
- Cardiovascular Genetics Division, University of Utah School of MedicineSalt Lake City, UT, USA (NHLBI Family Heart Study)
| | - Wei Chen
- Tulane Center for Cardiovascular Health, Tulane University Health Sciences CenterNew Orleans, LA, USA (The Bogalusa Heart Study)
| | - Jeffrey P Gardner
- Center of Human Development and Aging, University of Medicine and Dentistry of New Jersey, New Jersey Medical SchoolNewark, NJ, USA
| | - Masayuki Kimura
- Center of Human Development and Aging, University of Medicine and Dentistry of New Jersey, New Jersey Medical SchoolNewark, NJ, USA
| | - Sathanur R Srinivasan
- Tulane Center for Cardiovascular Health, Tulane University Health Sciences CenterNew Orleans, LA, USA (The Bogalusa Heart Study)
| | - John H Eckfeldt
- Department of Laboratory Medicine and Pathology, University of MinnesotaMinneapolis, MN, USA (NHLBI Family Heart Study)
| | - Gerald S Berenson
- Tulane Center for Cardiovascular Health, Tulane University Health Sciences CenterNew Orleans, LA, USA (The Bogalusa Heart Study)
| | - Abraham Aviv
- Center of Human Development and Aging, University of Medicine and Dentistry of New Jersey, New Jersey Medical SchoolNewark, NJ, USA
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Chen YJ, Campbell HG, Wiles AK, Eccles MR, Reddel RR, Braithwaite AW, Royds JA. PAX8 Regulates Telomerase Reverse Transcriptase and Telomerase RNA Component in Glioma. Cancer Res 2008; 68:5724-32. [DOI: 10.1158/0008-5472.can-08-0058] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Abstract
Developmental arrest is one of the mechanisms responsible for the elevated levels of embryo demise during the first week of in vitro development. Approximately 10-15% of IVF embryos permanently arrest in mitosis at the 2- to 4-cell cleavage stage showing no indication of apoptosis. Reactive oxygen species (ROS) are implicated in this process and must be controlled in order to optimize embryo production. A stress sensor that can provide a key understanding of permanent cell cycle arrest and link ROS with cellular signaling pathway(s) is p66Shc, an adaptor protein for apoptotic-response to oxidative stress. Deletion of the p66Shc gene in mice results in extended lifespan, which is linked to their enhanced resistance to oxidative stress and reduced levels of apoptosis. p66Shc has been shown to generate mitochondrial H(2)O(2) to trigger apoptosis, but may also serve as an integration point for many signaling pathways that affect mitochondrial function. We have detected elevated levels of p66Shc and ROS within arrested embryos and believe that p66Shc plays a central role in regulating permanent embryo arrest. In this paper, we review the cellular and molecular aspects of permanent embryo arrest and speculate on the mechanism(s) and etiology of this method of embryo demise.
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Affiliation(s)
- D H Betts
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada N1G 2W1.
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Betts DH, Perrault SD, King WA. Low oxygen delays fibroblast senescence despite shorter telomeres. Biogerontology 2007; 9:19-31. [PMID: 17952625 DOI: 10.1007/s10522-007-9113-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2007] [Accepted: 10/09/2007] [Indexed: 01/29/2023]
Abstract
It has been widely accepted that telomere shortening acts as a cell division counting mechanism that beyond a set critical length signals cells to enter replicative senescence. In this study, we demonstrate that by simply lowering the oxygen content of the cell culture environment 10-fold (20-2%) extends the replicative lifespan of fetal bovine fibroblasts at least five-times (30-150 days). Although, low oxygen fibroblasts display a slightly slower rate (P > 0.05) of telomere attrition than their high oxygen counterparts (171 bp versus 182 bp/PD), late passage fibroblasts (>50 PD) that have extended their replicative capacity under low oxygen conditions exhibited significantly (P < 0.05) shorter telomere lengths (11,135 +/- 467 bp) compared to senescent cells (25-34 PD) cultured under high oxygen conditions (14,827 +/- 1173 bp). There was a significant increase (P < 0.05) in chromosomal abnormalities with continual cell division under both high and low oxygen environments, however, fibroblasts displayed a significant reduction (P < 0.001) in chromosomal abnormalities at low oxygen tensions compared to those under 20% oxygen. These apparent protective effects on telomere shortening, delayed senescence and reduced chromosomal aberrations may be attributed to the up-regulation of telomerase activity observed for fibroblasts cultured under low oxygen. These results are consistent with the idea that a critically short telomere length may not be the sole trigger of replicative senescence, but may be regulated by the integrity of telomere structure itself and/or the amount of oxidative DNA damage in the cell.
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Affiliation(s)
- Dean H Betts
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada, N1G 2W1.
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Chen JH, Hales CN, Ozanne SE. DNA damage, cellular senescence and organismal ageing: causal or correlative? Nucleic Acids Res 2007; 35:7417-28. [PMID: 17913751 PMCID: PMC2190714 DOI: 10.1093/nar/gkm681] [Citation(s) in RCA: 333] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2007] [Revised: 08/16/2007] [Accepted: 08/17/2007] [Indexed: 01/07/2023] Open
Abstract
Cellular senescence has long been used as a cellular model for understanding mechanisms underlying the ageing process. Compelling evidence obtained in recent years demonstrate that DNA damage is a common mediator for both replicative senescence, which is triggered by telomere shortening, and premature cellular senescence induced by various stressors such as oncogenic stress and oxidative stress. Extensive observations suggest that DNA damage accumulates with age and that this may be due to an increase in production of reactive oxygen species (ROS) and a decline in DNA repair capacity with age. Mutation or disrupted expression of genes that increase DNA damage often result in premature ageing. In contrast, interventions that enhance resistance to oxidative stress and attenuate DNA damage contribute towards longevity. This evidence suggests that genomic instability plays a causative role in the ageing process. However, conflicting findings exist which indicate that ROS production and oxidative damage levels of macromolecules including DNA do not always correlate with lifespan in model animals. Here we review the recent advances in addressing the role of DNA damage in cellular senescence and organismal ageing.
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Affiliation(s)
- Jian-Hua Chen
- Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QR, UK.
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Kondoh K, Tsuji N, Asanuma K, Kobayashi D, Watanabe N. Inhibition of estrogen receptor β-mediated human telomerase reverse transcriptase gene transcription via the suppression of mitogen-activated protein kinase signaling plays an important role in 15-deoxy-Δ12,14-prostaglandin J2-induced apoptosis in cancer cells. Exp Cell Res 2007; 313:3486-96. [PMID: 17706193 DOI: 10.1016/j.yexcr.2007.06.028] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2007] [Revised: 06/23/2007] [Accepted: 06/25/2007] [Indexed: 01/05/2023]
Abstract
The nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR)-gamma plays a role in cancer development in addition to its role in glucose metabolism. The natural ligand of PPAR-gamma, namely, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), has been shown to possess antineoplastic activity in cancer cells. However, the mechanism underlying its antineoplastic activity remains to be elucidated. Inhibition of the expression of human telomerase reverse transcriptase (hTERT), a major determinant of telomerase activity, reportedly induces rapid apoptosis in cancer cells. In this study, we investigated the effect of 15d-PGJ(2) on hTERT expression. We found that 15d-PGJ(2) induced apoptosis in the MIAPaCa-2 pancreatic cancer cells and dose-dependently decreased hTERT mRNA and protein expression. Down-regulation of hTERT expression by hTERT-specific small inhibitory RNA also induced apoptosis. Furthermore, 15d-PGJ(2) attenuated the DNA binding of estrogen receptor (ER). MIAPaCa-2 expressed only ERbeta, and although its expression did not decrease due to 15d-PGJ(2), its phosphorylation was suppressed. Additionally, a mitogen-activated protein kinase (MAPK) kinase inhibitor decreased ERbeta phosphorylation, and 15d-PGJ(2) attenuated MAPK activity. We conclude that hTERT down-regulation by 15d-PGJ(2) plays an important role in the proapoptotic property of the latter. Furthermore, 15d-PGJ(2) inhibits ERbeta-mediated hTERT gene transcription by suppressing ERbeta phosphorylation via the inhibition of MAP kinase signaling.
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Affiliation(s)
- Kei Kondoh
- Department of Clinical Laboratory Medicine, Sapporo Medical University School of Medicine, Japan
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Shariftabrizi A, Eller MS. Telomere homolog oligonucleotides and the skin: current status and future perspectives. Exp Dermatol 2007; 16:627-33. [PMID: 17620088 DOI: 10.1111/j.1600-0625.2007.00580.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Affiliation(s)
- Ahmad Shariftabrizi
- Department of Dermatology, Boston University School of Medicine, Boston, MA 02118, USA
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45
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Yudoh K, Shishido K, Murayama H, Yano M, Matsubayashi K, Takada H, Nakamura H, Masuko K, Kato T, Nishioka K. Water-soluble C60 fullerene prevents degeneration of articular cartilage in osteoarthritis via down-regulation of chondrocyte catabolic activity and inhibition of cartilage degeneration during disease development. ACTA ACUST UNITED AC 2007; 56:3307-18. [PMID: 17907184 DOI: 10.1002/art.22917] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVE Studies have shown the roles of oxidative stress in the pathogenesis of osteoarthritis (OA) and induction of chondrocyte senescence during OA progression. The aim of this study was to examine the potential of a strong free-radical scavenger, water-soluble fullerene (C60), as a protective agent against catabolic stress-induced degeneration of articular cartilage in OA, both in vitro and in vivo. METHODS In the presence or absence of C60 (100 microM), human chondrocytes were incubated with interleukin-1beta (10 ng/ml) or H2O2 (100 microM), and chondrocyte activity was analyzed. An animal model of OA was produced in rabbits by resection of the medial meniscus and medial collateral ligament. Rabbits were divided into 5 subgroups: sham operation or treatment with C60 at 0.1 microM, 1 microM, 10 microM, or 40 microM. The left knee joint was injected intraarticularly with water-soluble C60 (2 ml), while, as a control, the right knee joint received 50% polyethylene glycol (2 ml), once weekly for 4 weeks or 8 weeks. Knee bone and cartilage tissue were prepared for histologic analysis. In addition, in the OA rabbit model, the effect of C60 (10 microM) on degeneration of articular cartilage was compared with that of sodium hyaluronate (HA) (5 mg/ml). RESULTS C60 (100 microM) inhibited the catabolic stress-induced production of matrix-degrading enzymes (matrix metalloproteinases 1, 3, and 13), down-regulation of matrix production, and apoptosis and premature senescence in human chondrocytes in vitro. In rabbits with OA, treatment with water-soluble C60 significantly reduced articular cartilage degeneration, whereas control knee joints showed progression of cartilage degeneration with time. This inhibitory effect was dose dependent, and was superior to that of HA. Combined treatment with C60 and HA yielded a significant reduction in cartilage degeneration compared with either treatment alone. CONCLUSION The results indicate that C60 fullerene is a potential therapeutic agent for the protection of articular cartilage against progression of OA.
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Affiliation(s)
- Kazuo Yudoh
- St. Marianna University School of Medicine, Kawasaki, Japan.
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46
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Sarkar D, Fisher PB. Polynucleotide phosphorylase: an evolutionary conserved gene with an expanding repertoire of functions. Pharmacol Ther 2006; 112:243-63. [PMID: 16733069 DOI: 10.1016/j.pharmthera.2006.04.003] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2006] [Accepted: 04/11/2006] [Indexed: 11/19/2022]
Abstract
RNA metabolism plays a seminal role in regulating diverse physiological processes. Polynucleotide phosphorylase (PNPase) is an evolutionary conserved 3',5' exoribonuclease, which plays a central role in RNA processing in bacteria and plants. Human polynucleotide phosphorylase (hPNPase old-35) was cloned using an inventive strategy designed to identify genes regulating the fundamental physiological processes of differentiation and senescence. Although hPNPase old-35 structurally and biochemically resembles PNPase of other species, targeted overexpression and inhibition studies reveal that hPNPase old-35 has evolved to serve more specialized functions in humans. The present review provides a global perspective on the structure and function of PNPase and then focuses on hPNPase old-35 in the contexts of differentiation and senescence.
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Affiliation(s)
- Devanand Sarkar
- Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY 10032, USA
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Jeyapalan JC, Saretzki G, Leake A, Tilby MJ, von Zglinicki T. Tumour-cell apoptosis after cisplatin treatment is not telomere dependent. Int J Cancer 2006; 118:2727-34. [PMID: 16381006 DOI: 10.1002/ijc.21675] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Cisplatin is a major chemotherapeutic agent, especially for the treatment of neuroblastoma. Telomeres with their sequence (TTAGGG)n are probable targets for cisplatin intrastrand cross-linking, but the role of telomeres in mediating cisplatin cytotoxicity is not clear. After exposure to cisplatin as single dose or continuous treatment, we found no loss of telomeres in either SHSY5Y neuroblastoma cells (telomere length, approximately 4 kbp), HeLa 229 cells (telomere length, 20 kbp) or in the acute lymphoblastic T cell line 1301 (telomere length, approximately 80 kbp). There was no induction of telomeric single strand breaks, telomeric overhangs were not degraded and telomerase activity was down-regulated only after massive onset of apoptosis. In contrast, cisplatin induced a delayed formation of DNA strand breaks and induced DNA damage foci containing gamma-H2A.X at nontelomeric sites. Interstitial DNA damage appears to be more important than telomere loss or telomeric damage as inducer of the signal pathway towards apoptosis and/or growth arrest in cisplatin-treated tumour cells.
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Affiliation(s)
- Jessie C Jeyapalan
- Henry Wellcome Biogerontology Laboratory, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
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Matthes E, Lehmann C, Stulich M, Wu Y, Dimitrova L, Uhlmann E, Janta-Lipinski MV. Potent inhibitory activity of chimeric oligonucleotides targeting two different sites of human telomerase. Oligonucleotides 2006; 15:255-68. [PMID: 16396620 DOI: 10.1089/oli.2005.15.255] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Suppression of telomerase activity in tumor cells has been considered as a new anticancer strategy. Here, we present chimeric oligonucleotides (chimeric ODNs) as a new type of telomerase inhibitor that contains differently modified oligomers to address two different sites of telomerase: the RNA template and a suggested protein motif. We have shown previously that phosphorothioate-modified oligonucleotides (PS ODNs) interact in a length-dependent rather than in a sequence-dependent manner, presumably with the protein part of the primer-binding site of telomerase, causing strong inhibition of telomerase. In the present study, we demonstrate that extensions of these PS ODNs at their 3'-ends with an antisense oligomer partial sequence covering 11 bases of the RNA template cause significantly increased inhibitory activity, with IC(50) values between 0.60 and 0.95 nM in a Telomeric Repeat Amplification Protocol (TRAP) assay based on U-87 cell lysates. The enhanced inhibitory activity is observed regardless of whether the antisense part is modified (phosphodiester, PO; 2'-O-methylribosyl, 2'-OMe/PO; phosphoramidate, PAM). However, inside intact U-87 cells, these modifications of the antisense part proved to be essential for efficient telomerase inhibition 20 hours after transfection. In particular, the chimeric ODNs containing PAM or 2'-OMe/PO modifications, when complexed with lipofectin, were most efficient telomerase inhibitors (ID(50) = 0.04 and 0.06 microM, respectively). In conclusion, ODNs of this new type emerged as powerful inhibitors of human telomerase and are, therefore, promising candidates for further investigations of the anticancer strategy of telomerase inhibition.
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Affiliation(s)
- Eckart Matthes
- Max-Delbrück-Centrum für Molekulare Medizin, D-13125 Berlin, Germany.
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Armstrong L, Saretzki G, Peters H, Wappler I, Evans J, Hole N, von Zglinicki T, Lako M. Overexpression of telomerase confers growth advantage, stress resistance, and enhanced differentiation of ESCs toward the hematopoietic lineage. Stem Cells 2006; 23:516-29. [PMID: 15790773 DOI: 10.1634/stemcells.2004-0269] [Citation(s) in RCA: 104] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Embryonic stem cells (ESCs) are capable of extended self-renewal and maintenance of pluripotency even after many population doublings. This is supported by high levels of telomerase activity and enhanced antioxidant protection in ESCs, both of which are downregulated during differentiation. To examine the role of telomerase for ESC self-renewal and differentiation, we overexpressed the reverse transcriptase subunit (Tert) of murine telomerase in ESCs. Increased telomerase activity enhances the self-renewal ability of the Tert-overexpressing ESCs, improves their resistance to apoptosis, and increases their proliferation. The differentiated progeny of wild-type ESCs express little Tert and show shortening of telomeric overhangs. In contrast, the progeny of Tert-overexpressing ESCs maintain high telomerase activity, as well as the length of G-rich overhangs. In addition, these cells accumulate lower concentrations of peroxides than wild-type cells, implying greater resistance to oxidative stress. Finally, differentiation toward hematopoietic lineages is more efficient as a result of the continued expression of Tert. Microarray analysis revealed that overexpression of Tert altered expression of a variety of genes required for extended self-renewal and lifespan. Our results suggest that telomerase functions as a "survival enzyme" in ESCs and its differentiated progeny by protecting the telomere cap and by influencing the expression patterns of stress response and defense genes. This results in improved proliferation of ESCs and more efficient differentiation, and these results might have profound consequences for stem cell-replacement therapies.
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Affiliation(s)
- L Armstrong
- Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, U.K
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50
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Poonepalli A, Balakrishnan L, Khaw AK, Low GKM, Jayapal M, Bhattacharjee RN, Akira S, Balajee AS, Hande MP. Lack of poly(ADP-ribose) polymerase-1 gene product enhances cellular sensitivity to arsenite. Cancer Res 2006; 65:10977-83. [PMID: 16322246 DOI: 10.1158/0008-5472.can-05-2336] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Arsenite (As3+) has long been known to induce cancer and other degenerative diseases. Arsenite exerts its toxicity in part by generating reactive oxygen species. Identification of genetic factors that contribute to arsenic mutagenicity and carcinogenicity is critical for the treatment and prevention of arsenic exposure in human population. As poly(ADP-ribose) polymerase (PARP) is critical for genomic DNA stability, role of PARP-1 was evaluated in arsenic-induced cytotoxic and genotoxic effects. Our study revealed that telomere attrition, probably owing to arsenite-induced oxidative stress, was much more pronounced in PARP-1-/- mouse embryonic fibroblasts (MEF; 40%) compared with PARP-1+/+ MEFs (10-20%). Correlation observed between telomere reduction and apoptotic death in PARP-1 null cells strongly indicates that the telomere attrition might be a trigger for enhanced apoptotic death after arsenite treatment. Elevated DNA damage detected by alkaline comet assay points to an impaired repair ability of arsenite-induced DNA lesions in PARP-1-/- MEFs. Consistent with elevated DNA damage, increased micronuclei induction reflecting gross genomic instability was also observed in arsenite-treated PARP-1-/- MEFs. Microarray analysis has revealed that arsenite treatment altered the expression of about 311 genes majority of which have known functions in cellular responses to stress/external stimulus and cell growth and/or maintenance. Our results suggest an important role for PARP-1 gene product in the maintenance of chromosome-genome stability in response to arsenite-induced DNA damage.
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Affiliation(s)
- Anuradha Poonepalli
- Genome Stability Laboratory, Department of Physiology, National University of Singapore
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