title: Molecular mechanisms for the p38-induced cellular senescence in normal human fibroblast.
abstract: We previously reported that TAK1, one of the mitogen-activated protein kinase kinase kinases (MAP3Ks), represses the transcription of the human telomerase reverse transcriptase (hTERT) gene in human cancer cells and induces cellular senescence in normal diploid human cells. On the basis of these results, we presumed a link between hTERT repression and the induction of cellular senescence. In this study, we identified the MAPK p38 as a downstream mediator of TAK1, which represses hTERT transcription. Further, we observed that hTERT expression was repressed in senescent normal human fibroblast, and was attenuated on treatment with SB203580, a p38-specific inhibitor, which suggests that p38 represses hTERT expression during cellular senescence. Next, we demonstrated that repression of hTERT, irrespective of the activation status of p38, is important for the induction of cellular senescence, by using hTERT-overexpressing cells and hTERT-knockdown cells. Our results suggested that p38 is activated during the serial passagings of normal human fibroblast, which results in the repression of hTERT transcription and induction of cellular senescence.
authors.affiliation: Graduate School of Systems Life Sciences, Kyushu University, Fukuoka 812-8581, Japan and Faculty of Agriculture, Kyushu University, Fukuoka 812-8581, Japan.
authors.forename: Gakuro
authors.initials: G
authors.lastname: Harada
authors.affiliation: Graduate School of Systems Life Sciences, Kyushu University, Fukuoka 812-8581, Japan and Faculty of Agriculture, Kyushu University, Fukuoka 812-8581, Japan.
authors.forename: Qian
authors.initials: Q
authors.lastname: Neng
authors.affiliation: Graduate School of Systems Life Sciences, Kyushu University, Fukuoka 812-8581, Japan and Faculty of Agriculture, Kyushu University, Fukuoka 812-8581, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Fujiki
authors.affiliation: Graduate School of Systems Life Sciences, Kyushu University, Fukuoka 812-8581, Japan and Faculty of Agriculture, Kyushu University, Fukuoka 812-8581, Japan Graduate School of Systems Life Sciences, Kyushu University, Fukuoka 812-8581, Japan and Faculty of Agriculture, Kyushu University, Fukuoka 812-8581, Japan katakura@grt.kyushu-u.ac.jp.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Katakura
mesh_terms: D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology* / Q000201:enzymology*; D006801:Humans; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D048051:p38 Mitogen-Activated Protein Kinases; C509186:TERT protein, human; D019098:Telomerase
keywords: TAK1; cellular senescence; hTERT; human fibroblast; p38