hTERT antagonizes p53-induced apoptosis independently of telomerase activity.
The p53 tumor suppressor controls cell growth and survival through transcriptional regulation of gene expression. Previously, we found that the human telomerase reverse transcriptase (hTERT) gene is downregulated by p53. To investigate if hTERT downregulation has a role in p53-dependent apoptosis, we tested if constitutive expression of telomerase could inhibit p53-induced apoptosis. Here we show that constitutive hTERT expression results in increased survival following activation of exogenous temperature-sensitive p53 in BL41 Burkitt lymphoma cells. Similarly, constitutive hTERT expression inhibited wild-type p53-dependent apoptosis in response to mitomycin C or 5-fluorouracil in HCT116 colon carcinoma cells carrying endogenous p53. A telomerase-inactive hTERT mutant was equally efficient in antagonizing p53-induced apoptosis. These findings support the notion that hTERT has antiapoptotic activity and demonstrate that p53-mediated downregulation of hTERT is critical for efficient p53-dependent apoptosis.
Rahman
Rubaiyat
R
Department of Oncology-Pathology, Cancer Center Karolinska, R8:04, Karolinska Institute, SE-171 76 Stockholm, Sweden.
Latonen
Leena
L
Wiman
Klas G
KG
D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002051:Burkitt Lymphoma / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002277:Carcinoma / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D003110:Colonic Neoplasms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D005472:Fluorouracil / Q000494:pharmacology; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D019098:Telomerase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013696:Temperature; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology
D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D016685:Mitomycin; D019098:Telomerase; D005472:Fluorouracil