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- Title
Induction of hTERT expression and phosphorylation by estrogen via Akt cascade in human ovarian cancer cell lines.
- Authors
Kimura, Akiko; Ohmichi, Masahide; Kawagoe, Jun; Kyo, Satoru; Mabuchi, Seiji; Takahashi, Toshifumi; Ohshima, Chika; Arimoto-Ishida, Emi; Nishio, Yukihiro; Inoue, Masaki; Kurachi, Hirohisa; Tasaka, Keiichi; Murata, Yuji
- Abstract
We examined the mechanism by which estrogen regulates telomerase activity in Caov-3 human ovarian cancer cell lines, which express ER, to determine whether the regulation affects the expression and/or phosphorylation of the telomerase catalytic subunit (hTERT). 17ß-Estradiol (E2) induced telomerase activity and hTERT expression. Transient expression assays using luciferase reporter plasmids containing various fragments of hTERT promoter showed that the estrogen-responsive element appeared to be partially responsible for the E2-induced activation of the hTERT promoter. Either pretreatment with a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, or transfection with a dominant-negative Akt attenuated the E2-induced activation of the hTERT promoter. In addition, estrogen induced the phosphorylation of I?B inhibitor protein via the Akt cascade, and cotransfection with a dominant-negative subunit of NF?B attenuated the response of the ERE-deleted hTERT promoter to E2. Moreover, E2 induced the phosphorylation of hTERT, the association of 14-3-3 protein and NF?B with hTERT, and nuclear accumulation of hTERT in an Akt-dependent manner. These results indicate that E2 induces telomerase activity not only by transcriptional regulation of hTERT via an ERE-dependent mechanism and a PI3K/Akt/NF?B cascade, but also by post-transcriptional regulation via Akt-dependent phosphorylation of hTERT. Thus, the phosphorylation of Akt is a key event in the induction of telomerase activity by E2 in human ovarian cancer cells.Oncogene (2004) 23, 4505-4515. doi:10.1038/sj.onc.1207582 Published online 29 March 2004
- Subjects
TELOMERASE; OVARIAN cancer; PHOSPHORYLATION; CANCER cells; CELL lines; GENETIC transcription
- Publication
Oncogene, 2004, Vol 23, Issue 26, p4505
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1207582