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

Oncogene volume 23, pages 4505–4515 (2004)Cite this article

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). 17β-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 IκB inhibitor protein via the Akt cascade, and cotransfection with a dominant-negative subunit of NFκB 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 NFκB 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/NFκB 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.

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Acknowledgements

We are grateful to Dr Takashi Tsuruo (Institute of Molecular and Cellular Biosciences, University of Tokyo, Japan) for providing pCR3 vector, pCR3-hTERT-HA, and GST-14-3-3-3θ constructs, Dr Gourisankar Ghosh (Department of Chemistry and Biochemistry, University of California, San Diego, USA) for providing pCR-FLAG-p50 and pCR-FLAG-p50ΔNLS constructs, Dr Michael E Greenberg and Dr Sandeep R Datta (Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, USA) for the gift of the vectors encoding the various forms of Akt.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Osaka University Medical School, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan

    Akiko Kimura, Masahide Ohmichi, Seiji Mabuchi, Emi Arimoto-Ishida, Yukihiro Nishio, Keiichi Tasaka & Yuji Murata

  2. Department of Obstetrics and Gynecology,

    Masahide Ohmichi, Jun Kawagoe, Toshifumi Takahashi & Hirohisa Kurachi

  3. Yamagata University, School of Medicine, 2-2-2 Iidanishi, Yamagata, 990-9585, Japan

    Masahide Ohmichi, Jun Kawagoe, Toshifumi Takahashi & Hirohisa Kurachi

  4. Department of Obstetrics and Gynecology, Kanazawa University Medical School, 13-1, Takaramachi Kanazawa-shi, Ishikawa, 920-8640, Japan

    Satoru Kyo & Masaki Inoue

  5. Division of Nursing, Yamagata University, School of Medicine, 2-2-2 Iidanishi, Yamagata, 990-9585, Japan

    Chika Ohshima

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Correspondence to Masahide Ohmichi.

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Kimura, A., Ohmichi, M., Kawagoe, J. et al. Induction of hTERT expression and phosphorylation by estrogen via Akt cascade in human ovarian cancer cell lines. Oncogene 23, 4505–4515 (2004). https://doi.org/10.1038/sj.onc.1207582

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