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

Heike Laman1, Juan M Funes, Hongtao Ye

  • 1Cancer Research UK, Viral Oncology Group, Wolfson Institute for Biomedical Research, University College London, London, UK. hl316@cam.ac.uk

The EMBO Journal
|August 13, 2005
PubMed

Insights

The F-box protein Fbxo7 specifically binds and regulates cyclin D/cdk6 complexes, promoting cell cycle entry. Fbxo7 overexpression transforms cells and suggests a proto-oncogenic role in human cancers.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Oncology

Background:

  • D-type cyclins and cyclin-dependent kinases (CDKs) facilitate cell cycle entry but have indistinguishable biochemical properties.
  • Tissue-specific functions of D-type cyclins and CDKs are known, yet their specific interactions remain unclear.

Purpose of the Study:

  • To investigate the role of F-box protein Fbxo7 in regulating D-type cyclin/CDK complexes.
  • To determine if Fbxo7 has a specific interaction with D-type cyclins and their CDK partners.
  • To assess the potential oncogenic role of Fbxo7 in cell transformation and cancer.

Main Methods:

  • In vitro and in vivo interaction studies between Fbxo7, D-type cyclins, and CDKs.
  • Fbxo7 knockdown and overexpression experiments in murine fibroblasts.
  • Assessment of cell cycle activity, E2F activity, and tumorigenicity in athymic nude mice.
  • Analysis of Fbxo7 expression in human epithelial tumors and normal tissues.

Main Results:

  • Fbxo7 specifically binds to cyclin D and distinguishes cdk6 as its binding partner among D-type cyclin-binding CDKs.
  • Fbxo7 regulates cyclin D/cdk6 complex activity, with knockdown decreasing and overexpression increasing activity and E2F activity.
  • Fbxo7 overexpression induces transformation of murine fibroblasts and renders them tumorigenic, a phenotype dependent on cdk6.
  • Fbxo7 is highly expressed in epithelial tumors but not in normal tissues.

Conclusions:

  • Fbxo7 acts as a specific regulator of cyclin D/cdk6 complexes, influencing cell cycle progression.
  • Fbxo7 possesses proto-oncogenic properties, driving cell transformation and tumorigenesis through cdk6.
  • Elevated Fbxo7 expression in tumors suggests its potential involvement in human carcinogenesis.

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