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Cdk6–cyclin D3 activity in murine ES cells is resistant to inhibition by p16INK4a

Oncogene volume 23, pages 491–502 (2004)Cite this article

Abstract

Through a screen aimed at identifying genes that are specifically upregulated in embryomic stem (ES) cells but not primitive ectoderm, we identified cyclin D3. This was surprising since cyclin D activity is generally believed to be inactive in ES cells even though retinoblastoma tumor suppressor protein (pRb) accumulates in a predominantly hyperphosphorylated state. Cdk6 is the major catalytic partner for cyclin D3 in ES cells and exhibits robust pRb kinase activity that is downregulated during the early stages of ES embryoid body differentiation. To investigate the basis underlying the insensitivity of ES cells to ectopic p16 expression, we show that Cdk6–cyclin D3 complexes are not subject to inhibition by p16, similar to Cdk–viral cyclin complexes. These observations show that specificity exists between Cdk4/6–cyclin D complexes and their ability to be targeted by p16. Our data suggest that Cdk6–cyclin D3 activity in other cell types, including tumors, may also be refractory to p16-mediated growth inhibition and raises the possibility of additional specificity within the INK4 family.

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Acknowledgements

This work was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia, the Australian Research Council (ARC) through the Center for Molecular Genetics of Development and the National Breast Cancer Foundation. JW was supported by an Australian Post-Graduate Award. PC was supported by an NHMRC Industry Training Fellowship. SD acknowledges the support of the Georgia Research Alliance (GRA) and the Georgia Cancer Coalition.

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Authors and Affiliations

  1. Department of Molecular Biosciences, BresaGen Cell Therapy Program, Center for Molecular Genetics of Development, University of Adelaide, Adelaide, South Australia, Australia

    Renate Faast, Josephine White, Peter Cartwright, Lesley Crocker & Stephen Dalton

  2. Cancer Research Program, Garvan Institute of Medical Research, St Vincent's Hospital, Darlinghurst, New South Wales, Australia

    Boris Sarcevic

  3. Rhodes Center, University of Georgia, 425 River Road, Athens, Georgia, USA

    Stephen Dalton

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  1. Renate Faast
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Correspondence to Stephen Dalton.

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Faast, R., White, J., Cartwright, P. et al. Cdk6–cyclin D3 activity in murine ES cells is resistant to inhibition by p16INK4a. Oncogene 23, 491–502 (2004). https://doi.org/10.1038/sj.onc.1207133

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