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  • Original Paper
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Direct activation of telomerase by EGF through Ets-mediated transactivation of TERT via MAP kinase signaling pathway

Oncogene volume 21, pages 4071–4079 (2002)Cite this article

Abstract

Telomerase is a regulated enzyme and its activity is tightly associated with cell proliferation. The mechanisms of this association are unclear, but specific growth factors may regulate telomerase activity. The present study examines the effect of epidermal growth factor (EGF) on telomerase activity and identifies the signal transduction pathway involved in this process. EGF up-regulated telomerase activity in EGF receptor-positive cells after the activation of telomerase reverse transcriptase (TERT) mRNA expression. This activation was rapid, peaked after 6 or 12 h and was not blocked by the concurrent exposure to cycloheximide, suggesting a direct effect of EGF on TERT transcription. Transient expression assays revealed that EGF activates the hTERT promoter and that the proximal core promoter is responsible for this regulation. The activation of hTERT mRNA expression by EGF was specifically blocked by MEK inhibitor, and in vitro kinase assays demonstrated that ERK is activated in response to EGF. Transient expression assays using mutant reporter plasmids revealed that an ETS motif located in the core promoter of hTERT is required for the EGF-induced transactivation of hTERT. Overexpression of wild type Ets in cells enhanced the EGF effect on hTERT transcription, while that of dominant negative Ets significantly repressed EGF action. These findings suggest that EGF activates telomerase through the direct activation of TERT transcription, in which the Ras/MEK/ERK pathway and Ets factor play major roles. Our data support the notion that growth factors directly regulate telomerase via specific signal transduction pathways.

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Acknowledgements

We thank Professor Wen-Chang Chang, National Cheng Kung University, Taiwan, for providing A-431 cells and Dr KE Boulukos, Universite de Nice, Faculte des Sciences, Nice, France for providing wild-type Ets and dominant-negative Ets expression vectors. We also thank Dr Koji Hisamoto for excellent technical support (Osaka University, Suita, Japan). This study was supported in part by a Grant-in Aid for the Second Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health and Welfare, Japan.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Kanazawa University, School of Medicine, 13-1, Takaramachi, Kanazawa, 920-8641, Ishikawa, Japan

    Yoshiko Maida, Satoru Kyo, Taro Kanaya, Zhuo Wang, Noriyuki Yatabe, Masaaki Tanaka, Mitsuhiro Nakamura & Masaki Inoue

  2. Department of Molecular Biology, Cancer Research Institute, Kanazawa University, 13-1, Takaramachi, Kanazawa, 920-8641, Ishikawa, Japan

    Seishi Murakami

  3. Department of Genetics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai Minato-ku, Tokyo, Japan

    Noriko Gotoh

  4. Department of Obstetrics and Gynecology, Osaka University School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 656-0871, Japan

    Masahide Ohmichi

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  1. Yoshiko Maida
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  2. Satoru Kyo
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Correspondence to Satoru Kyo.

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Maida, Y., Kyo, S., Kanaya, T. et al. Direct activation of telomerase by EGF through Ets-mediated transactivation of TERT via MAP kinase signaling pathway. Oncogene 21, 4071–4079 (2002). https://doi.org/10.1038/sj.onc.1205509

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