Ectopic mTERT expression in mouse embryonic stem cells does not affect differentiation but confers resistance to differentiation- and stress-induced p53-dependent apoptosis.
The fundamental role of telomerase is to protect telomere ends and to maintain telomere length during replication; hence, telomerase expression is high in stem cells but reduced upon differentiation. Recent studies indicate that telomerase might play other roles besides telomere maintenance. We have investigated the role of telomerase in cellular differentiation and death. Here, we show that ectopic expression of mouse telomerase catalytic subunit (mTERT) does not affect embryonic stem (ES) cell proliferation or differentiation in vitro, but protects ES cells against cell death during differentiation. Ectopic mTERT expression also confers resistance to apoptosis induced by oxidative stress and other genotoxic insults. This resistance depends on the catalytic activity of mTERT. Stress-signal-induced p53 accumulation and consequent p53-dependent apoptotic target gene expression was not affected by mTERT overexpression. However, although chemical inhibition of p53 by alpha-pifithrin reduced stress-induced apoptosis in vector-expressing cells, it did not significantly affect apoptosis in mTERT-expressing cells. Moreover, overexpression of mTERT in p53-/- ES cells did not confer further resistance to genotoxic insults, suggesting that mTERT might exert its protective effect by antagonizing the p53 pathway. Altogether, our findings indicate that ectopic mTERT expression in ES cells does not affect differentiation but confers resistance to apoptosis, and suggest that this strategy might be used in improving the efficiency of stem-cell therapies.
Lee
Ming Kei
MK
National Cancer Centre, 11, Hospital Drive, Singapore 169610, Republic of Singapore.
Hande
M Prakash
MP
Sabapathy
Kanaga
K
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D004268:DNA-Binding Proteins; D004622:Embryo, Mammalian / Q000166:cytology; D015870:Gene Expression; D051379:Mice; D018384:Oxidative Stress; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D019098:Telomerase