Novel interactions between FOXM1 and CDC25A regulate the cell cycle

Con Sullivan1, Youhong Liu, Jingjing Shen

  • 1Maine Institute for Human Genetics and Health, Brewer, Maine, United States of America.

Plos One
|December 15, 2012
PubMed

Insights

Forkhead box M1 (FOXM1) directly regulates CDC25A gene transcription and cell cycle progression. This study reveals FOXM1

Area of Science:

  • Molecular Biology
  • Cell Cycle Regulation
  • Gene Transcription

Background:

  • FOXM1 is a key regulator of cell cycle transitions and mitotic spindle assembly.
  • The precise mechanism by which FOXM1 regulates CDC25A transcription was previously unknown.
  • CDC25B and CDC25C were known to activate CDK1/cyclinB for FOXM1 phosphorylation.

Purpose of the Study:

  • To elucidate the mechanism of FOXM1-mediated CDC25A gene transcription.
  • To investigate the functional relationship between FOXM1 and CDC25A in cell cycle control.
  • To determine if CDC25A activates FOXM1 phosphorylation similarly to CDC25B and CDC25C.

Main Methods:

  • Promoter binding assays to assess direct FOXM1 regulation of CDC25A.
  • Analysis of E2F-dependent pathways.
  • Co-expression studies of FOXM1 and CDC25A.
  • Site-directed mutagenesis to investigate FOXM1 phosphorylation sites (T600, T611, T620).
  • Co-immunoprecipitation to detect protein interactions between FOXM1 and CDC25A.

Main Results:

  • FOXM1 directly binds to the CDC25A promoter, regulating its transcription.
  • FOXM1 transcriptional activity is synergistically enhanced by CDC25A co-expression, dependent on CDK1 phosphorylation of FOXM1 at T600, T611, and T620.
  • A novel interaction between FOXM1 and CDC25A was identified, enhanced by FOXM1 phosphorylation and dependent on CDC25A phosphatase activity.

Conclusions:

  • FOXM1 directly regulates CDC25A transcription through promoter binding and activation of E2F pathways.
  • CDC25A enhances FOXM1 transcriptional activity via CDK1-mediated phosphorylation, establishing a positive feedback loop.
  • A novel, phosphorylation-dependent interaction between FOXM1 and CDC25A provides new insights into cell cycle control mechanisms.

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