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Cdk6-cyclin D3 activity in murine ES cells is resistant to inhibition by p16(INK4a)

Renate Faast1, Josephine White, Peter Cartwright

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

Oncogene
|January 16, 2004
PubMed

Insights

Embryonic stem cells utilize cyclin D3-Cdk6, defying expectations of cyclin D inactivity. This complex resists p16 inhibition, suggesting potential implications for tumor growth and cell cycle regulation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

Background:

  • Embryonic stem (ES) cells possess unique regulatory mechanisms governing cell cycle progression.
  • Retinoblastoma tumor suppressor protein (pRb) is typically hyperphosphorylated in ES cells, yet cyclin D activity is presumed inactive.
  • The role of cyclin D-dependent kinases (CDKs) in ES cell regulation remains incompletely understood.

Purpose of the Study:

  • To identify genes specifically upregulated in ES cells compared to primitive ectoderm.
  • To investigate the activity and regulation of cyclin D3-Cdk6 complexes in ES cells.
  • To determine the basis for ES cell insensitivity to p16-mediated growth inhibition.

Main Methods:

  • Gene expression screening to identify upregulated genes in ES cells.
  • Biochemical assays to assess cyclin D3-Cdk6 complex formation and pRb kinase activity.
  • Analysis of p16INK4a inhibition on Cdk6-cyclin D3 activity.

Main Results:

  • Cyclin D3 was identified as specifically upregulated in ES cells.
  • Cdk6 was found to be the primary catalytic partner for cyclin D3, exhibiting robust pRb kinase activity.
  • Cdk6-cyclin D3 complexes demonstrated insensitivity to p16 inhibition, similar to viral cyclin complexes.
  • Specificity was observed between different Cdk4/6-cyclin D complexes and their susceptibility to p16.

Conclusions:

  • ES cells employ an active Cdk6-cyclin D3 complex for cell cycle regulation.
  • This complex's refractory nature to p16 suggests a mechanism for maintaining pluripotency.
  • The findings imply that Cdk6-cyclin D3 activity in other cell types, including tumors, may also resist p16-mediated growth inhibition.

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