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v-Jun stimulates both cdk2 kinase activity and G1/S progression via transcriptional repression of p21 CIP1

A Maclaren1, W Clark, E J Black

  • 1Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK. a.mclaren@beatson.ac.uk

Oncogene
|April 30, 2003
PubMed

Insights

Viral Jun (v-Jun) oncoprotein reduces p21 cyclin-dependent kinase inhibitor (CDK inhibitor) expression, disrupting cell cycle control. Restoring p21 levels inhibits v-Jun-induced cell proliferation, highlighting p21

Area of Science:

  • Oncogenic viral proteins
  • Cell cycle regulation
  • Gene expression control

Background:

  • Viral oncoproteins, such as v-Jun, can dysregulate cellular processes, including the cell cycle.
  • Cyclin-dependent kinase 2 (CDK2) activity is crucial for cell cycle progression and is tightly regulated.
  • p21 CIP1 is a key inhibitor of CDK2, playing a vital role in cell cycle arrest.

Purpose of the Study:

  • To investigate if v-Jun-induced cell cycle deregulation is mediated by aberrant expression of the CDK inhibitor p21 CIP1.
  • To elucidate the mechanisms by which v-Jun affects p21 CIP1 expression.
  • To determine the functional significance of altered p21 CIP1 levels in v-Jun-transformed cells.

Main Methods:

  • Quantitative analysis of p21 CIP1 mRNA and protein levels in v-Jun-transformed chick embryo fibroblasts (CEF).
  • Assessment of p21 CIP1 expression changes under growth-inhibitory conditions (serum deprivation, confluency) in normal and v-Jun-transformed CEF.
  • Functional assays involving ectopic p21 CIP1 expression in v-Jun-transformed CEF to measure CDK2 activity and cell cycle progression.
  • Analysis of p21 CIP1 promoter activity and p53 involvement using promoter mutants and transcriptional assays.

Main Results:

  • v-Jun transformation significantly reduces basal p21 CIP1 mRNA and protein expression in CEF.
  • v-Jun inhibits the normal induction of p21 CIP1 expression during serum deprivation or confluency.
  • Reintroduction of p21 CIP1 into v-Jun-transformed CEF suppresses CDK2 activity and halts cell cycle progression.
  • v-Jun represses p21 CIP1 gene transcription through both p53-dependent and -independent pathways.

Conclusions:

  • Aberrant downregulation of p21 CIP1 is a key mechanism by which v-Jun disrupts cell cycle control.
  • Restoring p21 CIP1 expression can counteract the proliferative effects of v-Jun, suggesting therapeutic potential.
  • v-Jun employs complex transcriptional mechanisms, involving both p53 and other factors, to suppress p21 CIP1 expression.

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