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Posttranslational regulation of the retinoblastoma gene family member p107 by calpain protease

Oncogene volume 18, pages 1789–1796 (1999)Cite this article

Abstract

The retinoblastoma protein plays a critical role in regulating the G1/S transition. Less is known about the function and regulation of the homologous pocket protein p107. Here we present evidence for the posttranslational regulation of p107 by the Ca2+-activated protease calpain. Three negative growth regulators, the HMG-CoA reductase inhibitor lovastatin, the antimetabolite 5-fluorouracil, and the cyclic nucleotide dibutyryl cAMP were found to induce cell type-specific loss of p107 protein which was reversible by the calpain inhibitor leucyl-leucyl-norleucinal but not by the serine protease inhibitor phenylmethylsulfonylfluoride, caspase inhibitors, or lactacystin, a specific inhibitor of the 26S proteasome. Purified calpain induced Ca2+-dependent p107 degradation in cell lysates. Transient expression of the specific calpain inhibitor calpastatin blocked the loss of p107 protein in lovastatin-treated cells, and the half-life of p107 was markedly lengthened in lovastatian-treated cells stably transfected with a calpastatin expression vector versus cells transfected with vector alone. The data presented here demonstrate down-regulation of p107 protein in response to various antiproliferative signals, and implicate calpain in p107 posttranslational regulation.

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Acknowledgements

We thank Mr Alfred W Alberts, Merck and Company, Inc., for generously providing lovastatin. We are grateful to Dr Frederic Kaye for critical review of the manuscript.

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Author notes

  1. Joung Soon Jang

    Present address: Department of Internal Medicine, Gyeong Sang National University College of Medicine and Gyeong Sang Institute of Cancer Research, Chinju, 660-280, Korea

Authors and Affiliations

  1. Division of Clinical Sciences, Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Joung Soon Jang, Su Jae Lee, Yung Hyun Choi, PhuongMai Nguyen, Jeen Lee, Sang-Gu Hwang & Jane B Trepel

  2. Division of Basic Sciences, Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Ming-Lei Wu & Pierre A Henkart

  3. National Kyoto Hospital, 612, Kyoto, Japan

    Emiko Takano

  4. Nagoya University, 464-01, Nagoya, Japan

    Masatoshi Maki

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Jang, J., Lee, S., Choi, Y. et al. Posttranslational regulation of the retinoblastoma gene family member p107 by calpain protease. Oncogene 18, 1789–1796 (1999). https://doi.org/10.1038/sj.onc.1202497

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