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Activation of cyclin D1 expression by the ERK5 cascade

Oncogene volume 22, pages 5387–5398 (2003)Cite this article

Abstract

Transcriptional activation of the cyclin D1 gene is a key step in cell proliferation. Accordingly, cyclin D1 overexpression is frequently an early step in neoplastic transformation, particularly in mammary epithelium. Numerous studies have linked elevated cyclin D1 promoter activity to a sustained activation of the ERK1/2 cascade. Here we show that the ERK5 cascade, a distinct mitogen-induced MAPK pathway, can also drive cyclin D1 expression. In CCL39 cells, serum induces a strong, prolonged peak of ERK1/2 and ERK5 phosphorylation, and subsequently elevates cyclin D1 mRNA and protein levels. Overexpression of constitutively active MEK5 and wt ERK5 induces a cyclin D1 reporter gene (D1 −973-luciferase) at least as well as constitutively active MEK1. Activation is blocked by kinase-dead mutants of ERK5 and ERK2, respectively. Mutation of the CRE at −50 in the cyclin D1 promoter decreases activation by the ERK5 but not the ERK1/2 cascade. Importantly, expression of kinase-dead ERK5 diminishes endogenous cyclin D1 protein induction by serum in CCL39 cells and the breast cancer cell lines MCF-7 and HS579. These data identify the cyclin D1 gene as a novel target of the ERK5 cascade, an observation with important implications in cancers involving cyclin D1 deregulation.

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Acknowledgements

We are indebted to the many people cited in the Materials and methods section who provided plasmids and cell lines, and would especially like to thank V Dulic for his helpful comments and generosity in providing the affinity-purified cyclin D1 polyclonal antiserum. We thank A Le Cam, J-M Blanchard, E Kremer and C Sardet for their critical comments on the manuscript, and we thank our colleagues in the IGMM, in particular A Gartland, for their support during the course of this study. R Mulloy was a Chateaubriand fellow and gratefully thanks the Sociéte Française de Cancer for a short-term fellowship. This work was supported in part by the CNRS and principally by grants from the Association pour la Recherche sur le Cancer (No 5890 and 5961).

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Authors and Affiliations

  1. Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, IFR 122, 1919 Route de Mende, Montpellier, Cedex 5, 34293, France

    Roseann Mulloy, Sara Salinas, Alexandre Philips & Robert A Hipskind

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  1. Roseann Mulloy
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  2. Sara Salinas
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  3. Alexandre Philips
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  4. Robert A Hipskind
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Correspondence to Robert A Hipskind.

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Mulloy, R., Salinas, S., Philips, A. et al. Activation of cyclin D1 expression by the ERK5 cascade. Oncogene 22, 5387–5398 (2003). https://doi.org/10.1038/sj.onc.1206839

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