Telomerase reverse transcriptase promotes cardiac muscle cell proliferation, hypertrophy, and survival

Oh, Hidemasa; Taffet, George E.; Youker, Keith A.; Entman, Mark L.; Overbeek, Paul A.; Michael, Lloyd H.; Schneider, Michael

doi:10.1073/pnas.191169098

Cited by 260 publications

(230 citation statements)

References 42 publications

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“…Taken together, these data indicate that in addition to its catalytic activity in telomeric DNA reverse transcription to lengthen telomeric DNA, hTERT also protects genomic DNA by physical interactions independent of its catalytic enzymatic activity in human cells. The pro-cellular survival function of hTERT is consistent with recent ®ndings that hTERT possesses an anti-apoptotic role in cultured neurons (Zhu et al, 2000), cardiac muscle cells (Oh et al, 2001) and vascular smooth muscle cells , and with the hypothesis that telomerase has a telomere capping function that is independent from telomere lengthening (Blackburn, 2000) and that telomerase is involved in complex interactions with other signaling pathways (Liu, 2000). Thus, telomerase is crucial once activated in regulating and maintaining both cell survival and proliferation not only by its enzymatic e ect on telomeric DNA synthesis but also by physical interactions to protect genome stability in continuously and discontinuously dividing cells.…”

Section: Discussionsupporting

confidence: 86%

TERT regulates cell survival independent of telomerase enzymatic activity

Cao¹,

He²,

Deb³

et al. 2002

Oncogene

197

139

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Human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, plays a pivotal role in the maintenance of telomeres and cell proliferation. Here we report that down-regulation of hTERT induces apoptosis independently of telomerase enzymatic activity in human breast cancer cells. Expression of a hTERT mutant lacking telomerase activity rescues the cells with lowered telomerase without inducing cell death. With similar patterns of subcellular distribution to that of the tumor suppressor protein p53 during mitosis, hTERT interacts with p53 and poly(ADP-ribose) polymerase (PARP). Decreasing p53 expression in intact cells worsens, and increasing p53 prevents, cell death induced by lowering hTERT. Thus, hTERT maintains cell survival and proliferation via both telomerase enzymatic activitydependent telomere lengthening and enzymatic activityindependent intermolecular interactions involving p53 and PARP.

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Section: Discussionsupporting

confidence: 86%

TERT regulates cell survival independent of telomerase enzymatic activity

Cao¹,

He²,

Deb³

et al. 2002

Oncogene

197

139

View full text Add to dashboard Cite

show abstract

“…2A). Telomerase reverse transcriptase is associated with self-renewal potential, down-regulated in adult myocardium, and sufficient to prolong cardiomyocyte cycling (30). By a telomeric repeat amplification protocol (30), we detected telomerase activity only in Sca-1 ϩ cells from adult heart but not in Sca-1 Ϫ cells, at levels similar to neonatal myocardium (Fig.…”

Section: Resultsmentioning

confidence: 81%

Cardiac progenitor cells from adult myocardium: Homing, differentiation, and fusion after infarction

Bradfute

Gallardo

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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1,616

1,247

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Potential repair by cell grafting or mobilizing endogenous cells holds particular attraction in heart disease, where the meager capacity for cardiomyocyte proliferation likely contributes to the irreversibility of heart failure. Whether cardiac progenitors exist in adult myocardium itself is unanswered, as is the question whether undifferentiated cardiac precursor cells merely fuse with preexisting myocytes. Here we report the existence of adult heart-derived cardiac progenitor cells expressing stem cell antigen-1. Initially, the cells express neither cardiac structural genes nor Nkx2.5 but differentiate in vitro in response to 5 -azacytidine, in part depending on Bmpr1a, a receptor for bone morphogenetic proteins. Given intravenously after ischemia͞reperfusion, cardiac stem cell antigen 1 cells home to injured myocardium. By using a Cre͞Lox donor͞ recipient pair (␣MHC-Cre͞R26R), differentiation was shown to occur roughly equally, with and without fusion to host cells. C ardiomyocytes can be formed, at least ex vivo, from diverse adult pluripotent cells (1-5). Apart from therapeutic implications and obviating ethical concerns aroused by embryonic stem cell lines, adult cardiac progenitor cells might provide an explanation distinct from cell cycle reentry, for the reported rare occurrence of cycling ventricular muscle cells (6). However, recent publications suggest the failure of certain stem cells' specification into neurons, skeletal muscle, and myocardium in vivo (7,8) and recommend greater conservatism in evaluating claims of adult stem cell plasticity, for cogent reasons (9-11).The rarity of cardiogenic conversion by endogenous hematopoietic cells (2, 12), requirements for intracardiac injection (3), or mobilization by cytokines (13), uncertain proof for myocytes of host origin in transplanted human hearts (14), and the confounding possibility of cell fusion after grafting in vivo (15, 16) highlight unsettled issues surrounding stem cell plasticity in heart disease. For donor cell types already in clinical studies, the predominant in vivo effect of bone marrow or endothelial progenitor cells may be neoangiogenesis, not cardiac specification (17, 18), and skeletal myoblasts, despite integration and survival, are confounded by arrhythmias, perhaps reflecting lack of transdifferentiation (19). These obstacles underscore the need to seek cardiac progenitor cells beyond the few known sources. Materials and MethodsFlow Cytometry and Magnetic Enrichment. A ''total'' cardiac population was isolated from 6-to 12-wk-old C57BL͞6 mice by coronary perfusion with 0.025% collagenase, as for viable adult mouse cardiomyocytes (20). More typically, a ''myocytedepleted'' population was prepared, incubating minced myocardium in 0.1% collagenase (30 min, 37°C), lethal to most adult mouse cardiomyocytes (20). Cells were then filtered through 70-m mesh. Bone marrow cells (21) were compared, with or without collagenase and filtration. Cells were labeled with stem cell antigen 1 (Sca-1)-phycoerythrin (PE), Sca-1-FITC, c-kit-PE; CD4-...

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“…In the present study, the absence of pericentrin expression in adult rat cardiomyocytes suggests that the former are not able to divide and they are terminally differentiated cells. Indeed, adult ventricular myocytes are refractory to cell cycle reentry for reasons that include the lack of telomerase activity (Oh et al, 2001). The discovery that adult cardiomyocytes may undergo apoptosis in physiologic conditions (Kang and Izumo, 2000) has proposed the existence of stem cells involved in the physiologic turnover of cardiac muscle tissue.…”

Section: Discussionmentioning

confidence: 99%

Research of cardiomyocyte precursors in adult rat heart

Bellafiore

Cappello

et al. 2006

Tissue and Cell

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Recent reports supported the existence of stem cells in adult hearts. However, phenotype and localization of these cells have not been completely described and it is unknown if cardiac regenerative potential differs from one subject to another. The aims of our work were to identify different populations of cardiac stem cells by the analysis of specific markers and to evaluate the expression variability of these markers in 12 adult rat hearts. The expression of CD9, taube nuss and nanog suggests the presence of stem cells from the earliest stages of embryogenesis in adult myocardium. Their different expression could be associated to the degree of stem cell differentiation. CD34 and c-Kit antibodies were used to detect stem cells committed to one or more specific tissue lineages and we found a strong immunoreactivity for CD34 exclusively in the endothelial cells and a low positivity for c-Kit in the interstitium and next to the vessels. Moreover, as c-Kit expression highly differed within all examined hearts, we suggest that cardiomyogenic potential is different among the various subjects. Undifferentiated cells with myogenic-committed phenotype expressing GATA-4 and nestin were found, respectively, in the interstitial and myocardial cells and in few interstitial cells. Therefore, the physiologic turn over of cardiomyocytes may occur in adult hearts as it has been shown in many others organs. The study of myogenic potential could be important to identify markers specific of stem cells in in vivo adult myocardium that may be used to purify these cells and evaluate their regenerative ability.

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Telomerase reverse transcriptase promotes cardiac muscle cell proliferation, hypertrophy, and survival

Cited by 260 publications

References 42 publications

TERT regulates cell survival independent of telomerase enzymatic activity

TERT regulates cell survival independent of telomerase enzymatic activity

Cardiac progenitor cells from adult myocardium: Homing, differentiation, and fusion after infarction

Research of cardiomyocyte precursors in adult rat heart

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