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p53-dependent repression of CDK4 translation in TGF-beta-induced G1 cell-cycle arrest

M E Ewen1, C J Oliver, H K Sluss

  • 1Dana-Farber Cancer Institute, Boston Massachusetts.

Genes & Development
|January 15, 1995
PubMed

Insights

Transforming growth factor beta 1 (TGF-beta 1) inhibits cyclin-dependent kinase 4 (cdk4) translation, causing cell-cycle arrest. Mutant p53 blocks this TGF-beta 1 effect, while wild-type p53 enhances it.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Transforming growth factor beta 1 (TGF-beta 1) induces G1 cell-cycle arrest.
  • Cyclin-dependent kinase 4 (cdk4) synthesis inhibition is a key mechanism in TGF-beta 1-mediated G1 arrest.
  • Altered cdk4 expression can lead to resistance against TGF-beta 1 signaling.

Purpose of the Study:

  • To investigate the role of cdk4 translation in TGF-beta 1-induced G1 arrest.
  • To elucidate the mechanism by which mutant and wild-type p53 influence cdk4 expression and TGF-beta 1 sensitivity.
  • To identify the regulatory elements involved in controlling cdk4 synthesis.

Main Methods:

  • Analysis of cdk4 expression and translation in response to TGF-beta 1.
  • Investigation of p53's effect on cdk4 regulation in various cellular contexts.
  • Examination of the 5'-untranslated region (5'-UTR) of the CDK4 messenger RNA (mRNA).

Main Results:

  • TGF-beta 1 was shown to down-regulate cdk4 expression by inhibiting its translation.
  • Mutant p53 conferred resistance to TGF-beta 1 by preventing cdk4 down-regulation.
  • Wild-type p53 was found to repress CDK4 translation.
  • Regulation of cdk4 translation by both p53 and TGF-beta 1 involves the 5'-UTR of the CDK4 mRNA.

Conclusions:

  • TGF-beta 1 controls G1 arrest through translational inhibition of cdk4.
  • p53 status significantly impacts cellular response to TGF-beta 1 by modulating cdk4 translation.
  • The 5'-UTR of CDK4 mRNA is a critical regulatory hub for both p53 and TGF-beta 1 pathways, influencing G1 progression.

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