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G1 phase arrest induced by Wilms tumor protein WT1 is abrogated by cyclin/CDK complexes

T Kudoh1, T Ishidate, M Moriyama

  • 1Department of Oncogene Research, Osaka University, Japan.

Proceedings of the National Academy of Sciences of the United States of America
|May 9, 1995
PubMed

Insights

The Wilms tumor-suppressor (WT1) gene product acts as a transcriptional repressor, inhibiting cell cycle progression. WT1

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • The Wilms tumor-suppressor gene (WT1) is crucial for normal urogenital development.
  • WT1 encodes a transcriptional repressor protein involved in cell cycle regulation.

Purpose of the Study:

  • To investigate the role of WT1 in cell cycle control.
  • To elucidate the mechanism by which WT1 inhibits cell cycle progression.

Main Methods:

  • Microinjection of WT1 cDNA into quiescent and G1-phase cells.
  • Analysis of cell cycle progression following WT1 introduction.
  • Assessing the impact of WT1 on cyclin/CDK complex activity and expression.

Main Results:

  • WT1 expression blocked serum-induced cell cycle entry into S phase.
  • WT1's inhibitory activity was modulated by an alternatively spliced region.
  • Overexpression of cyclin E/CDK2 or cyclin D1/CDK4 abrogated WT1's inhibitory effect.
  • WT1 overexpression downregulated CDK4- and CDK2-associated kinase activities without altering protein levels.

Conclusions:

  • WT1 acts as a cell cycle inhibitor by downregulating cyclin/CDK complex activity.
  • Alternative splicing of WT1 influences its cell cycle regulatory function.
  • WT1's mechanism involves the inhibition of key cell cycle kinases, suggesting a role in cell cycle checkpoints.

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