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Phosphorylation by p38 MAP kinase is required for E2F1 degradation and keratinocyte differentiation

Oncogene volume 28, pages 52–62 (2009)Cite this article

Abstract

The transcription factor E2F1 plays key roles in skin homeostasis, and is essential for normal keratinocyte proliferation and epidermal regeneration after injury. We have previously established that, in differentiating keratinocytes, E2F1 activity is controlled by nuclear export and subsequent degradation. These events are triggered by differentiation-induced stimulation of protein kinase C and p38 mitogen-activated protein kinase (MAPK). However, the mechanisms that induce E2F1 export from the nucleus and the role of p38 MAPK in this process are poorly understood. We now describe a novel regulatory pathway for E2F1, which involves phosphorylation by p38. We demonstrate that E2F1 forms complexes with active p38 through regions that exclude the N-terminus of this transcription factor, and that p38 activity is a major contributor to the phosphorylation status of E2F1 in keratinocytes. Using in vitro kinase assays, we identified Ser403 and Thr433 as the residues phosphorylated by p38. The biological significance of these observations is underscored by the inability of E2F1 mutants lacking one or both of these residues to be exported from the nucleus and degraded when keratinocytes receive differentiation stimuli, which results in impaired keratinocyte maturation.

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Acknowledgements

We thank A Pajak for technical assistance. This work was supported by grants to LD from the Canadian Institutes of Health Research and from the Natural Sciences and Engineering Research Council of Canada (NSERC). During these studies, IAI held research studentships from the Terry Fox Foundation, through an award from National Cancer Institute of Canada, and from the Canadian Institutes of Health Research Training Program in Cancer Research and Technology Transfer.

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Author notes

  1. I A Ivanova

    Present address: 3Current address: Department of Pathology, University Medical Centre, Utrecht 3584, CX Utrecht, The Netherlands.,

Authors and Affiliations

  1. Department of Physiology and Pharmacology, and Regulatory Biology and Functional Genomics Research Group, Siebens-Drake Research Institute, University of Western Ontario, London, ON, Canada

    I A Ivanova, K-A Nakrieko & L Dagnino

  2. Department of Paediatrics, Child Health Research Institute and Lawson Health Research Institute, University of Western Ontario, London, ON, Canada

    L Dagnino

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  1. I A Ivanova
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  2. K-A Nakrieko
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  3. L Dagnino
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Correspondence to L Dagnino.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Ivanova, I., Nakrieko, KA. & Dagnino, L. Phosphorylation by p38 MAP kinase is required for E2F1 degradation and keratinocyte differentiation. Oncogene 28, 52–62 (2009). https://doi.org/10.1038/onc.2008.354

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