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Hdm2 negatively regulates telomerase activity by functioning as an E3 ligase of hTERT

Oncogene volume 29, pages 4101–4112 (2010)Cite this article

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Abstract

In this study, we identified posttranslational regulation of human telomerase reverse-transcriptase (hTERT) by the E3 ligase Hdm2. The telomerase activity generated by exogenous hTERT in U2OS cells was reduced on adriamycin treatment. The overexpressed levels of hTERT were also decreased under the same conditions. These processes were reversed by treatment with a proteasome inhibitor or depletion of Hdm2. Furthermore, intrinsic telomerase activity was increased in HCT116 cells with ablation of Hdm2. Immunoprecipitation analyses showed that hTERT and Hdm2 bound to each other in multiple domains. Ubiquitination analyses showed that Hdm2 could polyubiquitinate hTERT principally at the N-terminus, which was further degraded in a proteasome-dependent manner. An hTERT mutant with all five lysine residues at the N-terminus of hTERT that mutated to arginine became resistant to Hdm2-mediated ubiquitination and degradation. In U2OS cells, depletion of Hdm2 or addition of the Hdm2-resistant hTERT mutant strengthened the cellular protective effects against apoptosis. Similar results were obtained with the Hdm2-stable H1299 cell line. These observations indicate that Hdm2 is an E3 ligase of hTERT.

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Acknowledgements

This work was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (0820110) and by a grant of the Korea Healthcare technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A080333).

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Author notes

  1. W Oh

    Present address: 5Current address: Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.,

  2. W Oh and E-W Lee: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, Korea

    W Oh, E-W Lee, M-R Yang, A Ko & J Song

  2. Department of Biological Science, Sungkyunkwan University, Suwon, Korea

    D Lee, C-H Yoon, Y-S Bae & C Y Choi

  3. Department of Biochemistry, Yonsei University, Seoul, Korea

    H-W Lee

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Oh, W., Lee, EW., Lee, D. et al. Hdm2 negatively regulates telomerase activity by functioning as an E3 ligase of hTERT. Oncogene 29, 4101–4112 (2010). https://doi.org/10.1038/onc.2010.160

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