Induction of hTERT expression and phosphorylation by estrogen via Akt cascade in human ovarian cancer cell lines.

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). 17beta-Estradiol (E(2)) 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 E(2)-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 E(2)-induced activation of the hTERT promoter. In addition, estrogen induced the phosphorylation of IkappaB inhibitor protein via the Akt cascade, and cotransfection with a dominant-negative subunit of NFkappaB attenuated the response of the ERE-deleted hTERT promoter to E(2). Moreover, E(2) induced the phosphorylation of hTERT, the association of 14-3-3 protein and NFkappaB with hTERT, and nuclear accumulation of hTERT in an Akt-dependent manner. These results indicate that E(2) induces telomerase activity not only by transcriptional regulation of hTERT via an ERE-dependent mechanism and a PI3K/Akt/NFkappaB 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 E(2) in human ovarian cancer cells.

• Authors: Akiko Kimura, Masahide Ohmichi, Jun Kawagoe, Satoru Kyo, Seiji Mabuchi, Toshifumi Takahashi, Chika Ohshima, Emi Arimoto-Ishida, Yukihiro Nishio, Masaki Inoue, Hirohisa Kurachi, Keiichi Tasaka, Yuji Murata
• Journal: Oncogene (Oncogene) Vol. 23 Issue 26 Pg. 4505-15 (Jun 03 2004) ISSN: 0950-9232 [Print] England
• PMID: 15048073 (Publication Type: Journal Article)

Chemical References

• 14-3-3 Proteins
• Chromones
• DNA-Binding Proteins
• Enzyme Inhibitors
• Estrogens
• I-kappa B Proteins
• Morpholines
• NF-kappa B
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins
• Receptors, Estrogen
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Estradiol
• Tyrosine 3-Monooxygenase
• AKT1 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Telomerase

Topics

• 14-3-3 Proteins
• Cell Nucleus (metabolism)
• Chromones (pharmacology)
• DNA-Binding Proteins
• Enzyme Inhibitors (pharmacology)
• Estradiol (metabolism, pharmacology)
• Estrogens (metabolism, pharmacology)
• Female
• Gene Expression Regulation, Enzymologic
• Humans
• I-kappa B Proteins (drug effects, metabolism)
• Morpholines (pharmacology)
• NF-kappa B (metabolism)
• Ovarian Neoplasms (drug therapy, metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Phosphorylation
• Promoter Regions, Genetic
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins (genetics, metabolism)
• Proto-Oncogene Proteins c-akt
• Receptors, Estrogen (drug effects, metabolism)
• Signal Transduction
• Telomerase (drug effects, genetics, metabolism)
• Tumor Cells, Cultured
• Tyrosine 3-Monooxygenase (metabolism)