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Cyclin-dependent kinase 1 expression is inhibited by p16(INK4a) at the post-transcriptional level through the

W W Chien1, C Domenech, R Catallo

  • 1Université Claude Bernard Lyon 1, CNRS UMR 5239 ENS-HCL, Faculté de Médecine Lyon Sud, Oullins, France.

Oncogene
|December 21, 2010
PubMed

Insights

The p16(INK4a) protein inhibits CDK1 expression post-transcriptionally, impacting cell cycle regulation. This occurs via microRNA modulation, affecting CDK1 mRNA translation and offering new therapeutic targets.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • The p16(INK4a) protein is a key regulator of cell cycle progression, primarily by inhibiting cyclin-dependent kinases (CDKs) 4 and 6.
  • p16(INK4a) also influences other transcription factors like c-myc and nuclear factor-kappaB, indicating broader regulatory roles.

Purpose of the Study:

  • To investigate the effect of p16(INK4a) overexpression on CDK1 expression in p16(-/-), pRb(WT), and p53(WT) cell lines.
  • To elucidate the post-transcriptional mechanisms by which p16(INK4a) regulates CDK1, focusing on microRNA involvement.

Main Methods:

  • Overexpression of p16(INK4a) in MCF7 and U87 cell lines.
  • Analysis of CDK1 protein synthesis, mRNA levels, and protein half-life.
  • Luciferase assays to assess translational inhibition via the CDK1 3'-untranslated region (3'UTR).
  • TaqMan Human microRNA Array and reverse transcription-qPCR to analyze microRNA expression.
  • Luciferase assays to confirm miRNA interaction with CDK1-3'UTR.

Main Results:

  • p16(INK4a) overexpression led to a significant decrease in CDK1 protein expression.
  • CDK1 downregulation was attributed to post-transcriptional regulation, evidenced by unchanged mRNA levels and half-life.
  • The 3'UTR of CDK1 mRNA was identified as the mediator of translational inhibition.
  • Expression of specific microRNAs (miR-410 and miR-650) was altered, correlating with CDK1 changes.
  • miR-410 and miR-650 were shown to interact with the CDK1-3'UTR, inhibiting CDK1 expression.

Conclusions:

  • p16(INK4a) inhibits CDK1 expression at the post-transcriptional level, primarily through microRNA-mediated translational repression.
  • This mechanism involves specific microRNAs (miR-410, miR-650) interacting with the CDK1 3'UTR.
  • p16(INK4a) may regulate gene expression broadly by modulating transcription factor activity and subsequent microRNA expression balances.

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