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  • The EMBO Journal (2005) 24, 3104 - 3116
  • doi:10.1038/sj.emboj.7600775

Published online: 11 August 2005

Transforming activity of Fbxo7 is mediated specifically through regulation of cyclin D/cdk6

Heike Laman1,6, Juan M Funes1, Hongtao Ye2,3, Stephen Henderson1, Laura Galinanes-Garcia4, Eiji Hara4, Phillip Knowles5, Neil McDonald5 and Chris Boshoff1

  1. Cancer Research UK, Viral Oncology Group, Wolfson Institute for Biomedical Research, University College London, London, UK
  2. Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK
  3. Department of Pathology, Guangxi Medical University, Guangxi, China
  4. Division of Protein Information, Institute for Genome Research, University of Tokushima, Tokushima City, Japan
  5. Structural Biology Laboratory, Cancer Research UK, London Research Institute, London, UK and School of Crystallography, Birkbeck College, London, UK
  6. Present address: Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK

Correspondence to:

Heike Laman, Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK. Tel.: +44 1223 336 921; Fax: +44 1223 336 926; E-mail: hl316@cam.ac.uk

Received 7 April 2005; Accepted 18 July 2005

D cyclins (D1, D2 and D3) and their catalytic subunits (cyclin-dependent kinases cdk4 and cdk6) have a facilitating, but nonessential, role in cell cycle entry. Tissue-specific functions for D-type cyclins and cdks have been reported; however, the biochemical properties of these kinases are indistinguishable. We report that an F box protein, Fbxo7, interacted with cellular and viral D cyclins and distinguished among the cdks that bind D-type cyclins, specifically binding cdk6, in vitro and in vivo. Fbxo7 specifically regulated D cyclin/cdk6 complexes: Fbxo7 knockdown decreased cdk6 association with cyclin and its overexpression increased D cyclin/cdk6 activity and E2F activity. Fbxo7 interacted with p27, but its enhancement of cyclin D/cdk6 activity was p21/p27 independent. Fbxo7 overexpression transformed murine fibroblasts, rendering them tumorigenic in athymic nude mice. Transformed phenotypes were dependent on cdk6, as knockdown of cdk6 reversed them. Fbxo7 was highly expressed in epithelial tumors, but not in normal tissues, suggesting that it may have a proto-oncogenic role in human cancers.

  • Keywords:

    • cell cycle,
    • cdk6,
    • D cyclin,
    • Fbxo7,
    • transformation