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The α isoform of protein kinase C mediates phorbol ester-induced growth inhibition and p21cip1 induction in HC11 mammary epithelial cells

Oncogene volume 18, pages 6658–6666 (1999)Cite this article

Abstract

To clarify the roles of specific isoforms of PKC in regulating growth and cell cycle progression of the HC11 mammary epithelial cell line, we investigated the effects of activating endogenous PKC isoforms with the phorbol ester tumor promoter TPA, and also the effects of TPA on genetically engineered cells containing increased levels of individual PKC isoforms. We found that TPA treatment of HC11 cells induced a transient cell cycle arrest in G0/G1. Western blot analyses of the TPA treated cells provided evidence that the endogenous PKCα present in these cells mediated these effects. Indeed, derivatives of the HC11 cell line that inducibly overexpress an exogenous PKCα or ectopic PKCβ1 exhibited more marked growth inhibition by TPA than control cells. Immunohistochemical staining of cells following treatment with TPA revealed selective translocation of PKCα into the nucleus, whereas PKCβ1 remained in the cytoplasm. The transient arrest of HC11 cells following treatment with TPA was associated with marked induction of both p21cip1 mRNA and protein. This induction was exaggerated in the derivatives that overexpressed either PKCα or PKCβ1. Therefore, in mouse mammary epithelial cells activation of the endogenous PKCα can transiently arrest cells in G0/G1 which may be due, at least in part, to induction of the transcription of p21cip1.

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Acknowledgements

We are grateful for the excellent administrative assistance provided by Barbara Castro and the technical assistance provided by Ester Okin and Wang-Qui Xing. Susan Jaken generously provided the PKCβ1 antibody; M Gossen provided the pUHD plasmids; and Jae-Won Soh provided the mouse p21cip1 cDNA and valuable discussions. We also thank Hirofumi Yamamoto, Veronique Alvaro, Alessandro Sgambato and Fay Xing for their assistance. This research was supported by NCI Grant CA02656 and funds from the National Foundation for Cancer Research (to IB Weinstein). ED Slosberg was supported by NCI Cancer Training Grant T32CA09503 and a NIH Pre-Doctoral Training Grant T32GM07088.

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Authors and Affiliations

  1. Herbert Irving Comprehensive Cancer Center, Columbia University, HHSC 1509, 701 West 168th Street, New York, 10032, NY, USA

    Eric D Slosberg, Michael G Klein, Yao Yao, Edward Kyu-Ho Han, Ira Schieren & I Bernard Weinstein

  2. Novartis Pharmaceuticals Corporation, 556 Morris Avenue, Summit, 07901, New Jersey, NJ, USA

    Eric D Slosberg

  3. Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, 10461, NY, USA

    Michael G Klein

  4. Abbott Laboratories, 100 Abbott Park Road, Abbott Park, 60064, Illinois, IL, USA

    Edward Kyu-Ho Han

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Slosberg, E., Klein, M., Yao, Y. et al. The α isoform of protein kinase C mediates phorbol ester-induced growth inhibition and p21cip1 induction in HC11 mammary epithelial cells. Oncogene 18, 6658–6666 (1999). https://doi.org/10.1038/sj.onc.1203083

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