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v-Jun stimulates both cdk2 kinase activity and G1/S progression via transcriptional repression of p21 CIP1

Oncogene volume 22, pages 2383–2395 (2003)Cite this article

Abstract

Previous studies have shown that the viral Jun (v-Jun) oncoprotein induces marked alterations in cell cycle control, which are associated with, and may be caused by, increased cdk2 kinase activity. Since p21 CIP1 is an important regulator of cdk2, we investigated whether aberrant expression of this cyclin-dependent kinase inhibitor might contribute to cell cycle deregulation by v-Jun. We find that the basal levels of p21 CIP1 mRNA and protein expression are greatly reduced in chick embryo fibroblasts (CEF) transformed by v-Jun, and that v-Jun blocks the increases in p21 CIP1 expression that normally accompany growth inhibition induced by serum deprivation or confluency in untransformed CEF. Importantly, ectopic expression of p21 CIP1 in v-Jun-transformed CEF inhibits both cdk2 kinase activity and cell cycle progression, indicating that these alterations in p21 CIP1 expression are likely to be functionally significant for growth deregulation. We also investigated the mechanism through which v-Jun disturbs p21 CIP1 expression and the possible involvement of a known p21 CIP1 regulator, p53, as an intermediate in this process. This analysis revealed that repression is mediated primarily at the level of p21 CIP1 gene transcription, however the mechanism is complex; both p53-dependent and -independent mechanisms contribute as judged by analysis of p21 CIP1 promoter mutants and other assays of p53 transcriptional activity.

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Acknowledgements

This work is supported by Cancer Research UK. The authors thank the following for the provision of reagents—M Oren, X Wang, N Perkins, and K Ryan and J Wyke for comments on the manuscript.

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Authors and Affiliations

  1. Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow, G61 1BD

    A Maclaren, W Clark & E J Black

  2. Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK

    D A F Gillespie

  3. Division of Gene Regulation and Expression, School of Life Sciences, MSI/WTB Complex, Dow Street, University of Dundee, DD1 5EH, UK

    D Gregory

  4. Cancer Research UK Developmental Genetics Laboratory, Lincoln's Inn Fields, WC2A 3PX, UK

    H Fujii

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  1. A Maclaren
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Correspondence to A Maclaren.

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Maclaren, A., Clark, W., Black, E. et al. v-Jun stimulates both cdk2 kinase activity and G1/S progression via transcriptional repression of p21 CIP1. Oncogene 22, 2383–2395 (2003). https://doi.org/10.1038/sj.onc.1206329

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