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Involvement of protein kinase Cδ in contact-dependent inhibition of growth in human and murine fibroblasts

Oncogene volume 20, pages 5143–5154 (2001)Cite this article

Abstract

There is evidence that protein kinase C δ (PKCδ) is a tumor suppressor, although its physiological role has not been elucidated so far. Since important anti-proliferative signals are mediated by cell–cell contacts we studied whether PKCδ is involved in contact-dependent inhibition of growth in human (FH109) and murine (NIH3T3) fibroblasts. Cell–cell contacts were imitated by the addition of glutardialdehyde-fixed cells to sparsely seeded fibroblasts. Downregulation of the PKC isoforms α, δ, ε, and μ after prolonged treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA, 0.1 μM) resulted in a significant release from contact-inhibition in FH109 cells. Bryostatin 1 selectively prevented TPA-induced PKCδ-downregulation and reversed TPA-induced release from contact-inhibition arguing for a role of PKCδ in contact-inhibition. In accordance, the PKCδ specific inhibitor Rottlerin (1 μM) totally abolished contact-inhibition. Interestingly, immunofluorescence revealed a rapid translocation of PKCδ to the nucleus when cultures reached confluence with a peak in early-mid G1 phase. Nuclear translocation of PKCδ in response to cell–cell contacts could also be demonstrated after subcellular fractionation by Western blotting and by measuring PKCδ-activity after immunoprecipitation. Transient transfection of NIH3T3 cells with a dominant negative mutant of PKCδ induced a transformed phenotype. We conclude that PKCδ is involved in contact-dependent inhibition of growth.

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Acknowledgements

We thank Shigeo Ohno for kindly providing the dominant negative mutant of PKCδ. This work was supported by a grant from Deutsche Forschungsgemeinschaft Wi 727/3-2 and Graduiertenförderung des Landes Rheinland-Pfalz and is part of the PhD thesis of I Heit.

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Author notes

  1. Isabelle Heit

    Present address: Byk Gulden, Konstanz, 78467, Germany

  2. Raimund J Wieser

    Present address: innoTides GmbH, its, Baesweiler, 52499, Germany

  3. Thomas Herget

    Present address: Axxima Pharmaceuticals AG, Martinsried, 82152, Germany

Authors and Affiliations

  1. Institute of Toxicology, Johannes Gutenberg-University of Mainz, Mainz, 55131, Germany

    Isabelle Heit, Raimund J Wieser, Dagmar Faust, Monika Borchert-Stuhlträger, Franz Oesch & Cornelia Dietrich

  2. Institute of Physiological Chemistry, Johannes Gutenberg-University of Mainz, Mainz, 55131, Germany

    Thomas Herget

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Correspondence to Cornelia Dietrich.

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Heit, I., Wieser, R., Herget, T. et al. Involvement of protein kinase Cδ in contact-dependent inhibition of growth in human and murine fibroblasts. Oncogene 20, 5143–5154 (2001). https://doi.org/10.1038/sj.onc.1204657

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