TY - JOUR
T1 - TAK1 represses transcription of the human telomerase reverse transcriptase gene
AU - Fujiki, T.
AU - Miura, T.
AU - Maura, M.
AU - Shiraishi, H.
AU - Nishimura, S.
AU - Imada, Y.
AU - Uehara, N.
AU - Tashiro, K.
AU - Shirahata, S.
AU - Katakura, Y.
N1 - Funding Information:
We thank Dr K Matsumoto (Nagoya University, Japan) for providing us with pCMV-TAK1, pCMV-TAK1 (K63W), and pCMV-TAB1 (Yamaguchi et al., 1995; Shibuya et al., 1996); Dr RA Weinberg (Massachusetts Institute of Technology, MA, USA), for providing pCI-Neo-hTERT; Dr R Tjian (Howard Hughes Medical Institute), for providing pBS-Sp1-FL; Dr ST Smale (UCLA, Los Angeles, CA, USA), for providing GAL4-Sp1 (83−778); and Dr K Takahashi (Nihon University, Japan), for her technical advice. This work was supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science.
Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2007/8/9
Y1 - 2007/8/9
N2 - In human cells, telomerase activity is tightly regulated by the expression of its catalytic subunit, namely, the human telomerase reverse transcriptase (hTERT). However, the molecular mechanisms involved in the regulation of hTERT expression have not been completely clarified. We have previously reported that transforming growth factor β (TGF-β) represses the expression of the hTERT gene. In the present study, we demonstrated that TGF-β-activated kinase 1 (TAK1), originally identified as a mitogen-activated kinase kinase kinase, represses the hTERT core promoter activity in an E-box-independent manner, and it also represses the transcription of the hTERT gene in human lung adenocarcinoma cell line, A549 cells. This TAK1-induced repression was found to be caused by the recruitment of histone deacetylase to Sp1 at the hTERT promoter and a consequent reduction in the amount of acetylated histone H4 at the hTERT promoter. Finally, we demonstrated that TAK1 induces cellular senescence programs in normal human diploid cells. Thus, we assume that TAK1 triggers the repression mechanisms of the hTERT gene as a result of evoking cellular senescence programs. Considered together, TAK1 is thought to play a causative role in the determination of a finite replicative lifespan of normal and cancer cells.
AB - In human cells, telomerase activity is tightly regulated by the expression of its catalytic subunit, namely, the human telomerase reverse transcriptase (hTERT). However, the molecular mechanisms involved in the regulation of hTERT expression have not been completely clarified. We have previously reported that transforming growth factor β (TGF-β) represses the expression of the hTERT gene. In the present study, we demonstrated that TGF-β-activated kinase 1 (TAK1), originally identified as a mitogen-activated kinase kinase kinase, represses the hTERT core promoter activity in an E-box-independent manner, and it also represses the transcription of the hTERT gene in human lung adenocarcinoma cell line, A549 cells. This TAK1-induced repression was found to be caused by the recruitment of histone deacetylase to Sp1 at the hTERT promoter and a consequent reduction in the amount of acetylated histone H4 at the hTERT promoter. Finally, we demonstrated that TAK1 induces cellular senescence programs in normal human diploid cells. Thus, we assume that TAK1 triggers the repression mechanisms of the hTERT gene as a result of evoking cellular senescence programs. Considered together, TAK1 is thought to play a causative role in the determination of a finite replicative lifespan of normal and cancer cells.
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U2 - 10.1038/sj.onc.1210331
DO - 10.1038/sj.onc.1210331
M3 - Article
C2 - 17325661
AN - SCOPUS:34547751499
SN - 0950-9232
VL - 26
SP - 5258
EP - 5266
JO - Oncogene
JF - Oncogene
IS - 36
ER -
