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Ectopic expression of Cdk6 circumvents transforming growth factor-β mediated growth inhibition

Oncogene volume 20, pages 5888–5896 (2001)Cite this article

Abstract

Transforming growth factor-β (TGF-β) induced growth arrest of cells involves regulation of the activities of both D- and E-type cyclin kinase complexes thought to be mediated primarily by the regulation of p15Ink4b and p27Kip1 cyclin kinase inhibitors. We show here that TGF-β downregulates Cdk6 and that transient and stable expression of Cdk6 in Mv1Lu mink epithelial cells overrides TGF-β mediated arrest. The main effect of the ectopic Cdk6 expression was to sequester TGF-β induced p15Ink4b and to maintain more p27Kip1 in cyclin D-complexes preventing the complete shift of p27Kip1 to Cdk2 invoked by TGF-β. This led to the presence of an active cyclinD-Cdk6-p27Kip1 complex and partially active cyclin E-Cdk2 complex and resulted in the failure of TGF-β to fully arrest Mv1Lu cell growth. Though dominant negative Cdk6, expressed similarly in the cells, sequestered both p15Ink4b and p27Kip1, it lacks kinase activity and was unable to override the TGF-β arrest. The results demonstrate that downregulation of Cdk6 kinase is required for the enforcement of the G1-phase arrest by TGF-β and results in changes in association of the p15Ink4b and p27Kip1 inhibitors with D- and E-type cyclin kinase complexes.

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Acknowledgements

This work was supported by the Academy of Finland grants 32788 (M Laiho) and 44885 (Finnish Centre of Excellence Program 2000-2005), the University of Helsinki, Biocentrum Helsinki, Sigrid Juselius Foundation and the Finnish Cancer Foundation.

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  1. Department of Virology, Haartman Institute, University of Helsinki, Helsinki, FIN-00014, Finland

    Fan Zhang, Minna Taipale, Annamari Heiskanen & Marikki Laiho

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Correspondence to Marikki Laiho.

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Zhang, F., Taipale, M., Heiskanen, A. et al. Ectopic expression of Cdk6 circumvents transforming growth factor-β mediated growth inhibition. Oncogene 20, 5888–5896 (2001). https://doi.org/10.1038/sj.onc.1204745

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