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E2F1 stability is regulated by a novel-PKC/p38β MAP kinase signaling pathway during keratinocyte differentiation

Oncogene volume 25, pages 430–437 (2006)Cite this article

Abstract

E2F transcription factors regulate proliferation, differentiation, DNA repair and apoptosis. Tight E2F regulation is crucial for epidermal formation and regeneration. However, virtually nothing is known about the molecular events modulating E2F during epidermal keratinocyte differentiation. Elucidation of these events is essential to understand epidermal morphogenesis, transformation and repair. Here we show that, in differentiating keratinocytes, Ca2+-induced protein kinase C (PKC) activation downregulates E2F1 protein levels. Further, we have identified PKCδ and η as those isoforms specifically involved in induction of E2F1 proteasomal degradation. We also demonstrate that E2F1 downregulation by novel PKC isozymes requires activation of p38β mitogen-activated protein kinase (MAPK). This is the first example of regulation in the E2F transcription factor family by activation of PKC and MAPK in the context of biologically significant differentiation stimuli in epithelia.

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Acknowledgements

We thank Drs F Beier, S Li and D Litchfield for helpful comments on the manuscript, and H Dupuis for technical assistance. This work was supported by grants to LD from the National Science and Engineering Research Council of Canada, and the National Cancer Institute of Canada (NCIC) with funds from the Canadian Cancer Society and the Terry Fox Foundation, raised through the Terry Fox Run. IAI is a Research student of the Terry Fox Foundation, through an award from NCIC. SJAD is a CIHR New Investigator. During the development of this work, LD was a CIHR/Cancer Research Society Inc. New Investigator.

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, University of Western Ontario, London, N6A 5C1, Ontario, Canada

    I A Ivanova, S J A D'Souza & L Dagnino

  2. Department of Paediatrics, University of Western Ontario, London, N6A 5C1, Ontario, Canada

    L Dagnino

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  1. I A Ivanova
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  2. S J A D'Souza
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  3. L Dagnino
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Correspondence to L Dagnino.

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Ivanova, I., D'Souza, S. & Dagnino, L. E2F1 stability is regulated by a novel-PKC/p38β MAP kinase signaling pathway during keratinocyte differentiation. Oncogene 25, 430–437 (2006). https://doi.org/10.1038/sj.onc.1208999

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