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Calcineurin regulation of the mammalian G0/G1 checkpoint element, cyclin dependent kinase 4

Oncogene volume 19, pages 2820–2827 (2000)Cite this article

Abstract

Cyclin dependent kinase 4 (cdk4) activity is controlled by the binding of regulatory subunits and inhibitory factors, as well as tyrosine and serine/threonine phosphorylation. More recently the influence of calcium levels have been demonstrated. Using transient transfections in Jurkat cells, we observed specific binding between cdk4 and the calcium and calmodulin activated serine/threonine phosphatase, calcineurin. Furthermore, we demonstrated that the inhibition of the phosphatase activity of calcineurin with FK506 and cyclosporin A resulted in an overall increase in cdk4 kinase activity, suggesting that the phosphatase activity of calcineurin was inhibitory to the kinase activity of cdk4. In contrast, we were not able to observe a similar effect on the kinase activity of either cdk6 or cdk2, indicating that the phosphatase activity of calcineurin was specific for cdk4. In addition, using an in vitro phosphatase assay for calcineurin, we observed that the exogenous addition of calcineurin resulted in the dephosphorylation of cdk4, an event that downregulated the kinase activity of cdk4. Calcineurin could, therefore, play an opposing role to the action of the cyclin activating kinase complex, an enzyme that upregulates the kinase activity of cdk4, an important G0/G1 checkpoint element in mammalian cells.

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Acknowledgements

We would like to thank Mohammed Ladha for his invaluable help with cdk4, cdk6 and cdk2 in vitro kinase assays; Charles Sherr for providing the construct for GST-cdk4, Histidine tagged-Cyclin D2 and hemataglutinnin (HA)-tagged cdk4; Jim Koh for providing HA-tagged cdk6; and Peter Adams for providing the GST-RbC bacterial expression plasmid for the initial preparation of the substrate for cdk4 and cdk6 in vitro kinase assays. We would also like to thank the members of the Burakoff and DeCaprio laboratories for their helpful discussions. S Baksh is a recipient of the Medical Research Foundation of Canada post-doctoral fellowship and an Abrahams post-doctoral Fellow.

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Authors and Affiliations

  1. Department of Pediatric Oncology, Dana Farber Cancer Institute, 44 Binney Street, Boston, 02115, Massachusetts, MA, USA

    Shairaz Baksh

  2. Department of Adult Oncology, Dana Farber Cancer Institute, Boston, 02115, Massachusetts, MA, USA

    James A DeCaprio

  3. Department of Pediatrics, Harvard Medical School, Boston, 02115, Massachusetts, MA, USA

    Steven J Burakoff

  4. Department of Medicine, Harvard Medical School, Boston, MA. 02115, Massachusetts, USA

    Steven J Burakoff

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  1. Shairaz Baksh
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  2. James A DeCaprio
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Baksh, S., DeCaprio, J. & Burakoff, S. Calcineurin regulation of the mammalian G0/G1 checkpoint element, cyclin dependent kinase 4. Oncogene 19, 2820–2827 (2000). https://doi.org/10.1038/sj.onc.1203585

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