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The c-myc gene is a direct target of mammalian SWI/SNF-related complexes during differentiation-associated cell cycle

Norman G Nagl1, Daniel R Zweitzig, Bayar Thimmapaya

  • 1Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.

Cancer Research
|February 3, 2006
PubMed

Insights

Mammalian SWI/SNF complexes regulate cell proliferation by repressing c-myc expression during differentiation. This repression is essential for p21(WAF1/CIP1) induction, revealing a novel pathway for cell cycle control.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Mammalian SWI/SNF-related chromatin remodeling complexes are vital for cell differentiation, development, and tumor suppression.
  • These complexes regulate the cell cycle, including p21(WAF1/CIP1) kinase inhibitor induction and E2F-responsive promoter repression, often through pRb phosphorylation.
  • The precise role of SWI/SNF complexes in these regulatory pathways remains incompletely understood.

Purpose of the Study:

  • To elucidate the direct role of mammalian SWI/SNF-related complexes in cell cycle control during differentiation.
  • To investigate the involvement of SWI/SNF complexes in the regulation of c-myc expression.
  • To determine the relationship between c-myc regulation, p21(WAF1/CIP1) induction, and E2F-responsive gene repression by SWI/SNF complexes.

Main Methods:

  • Analysis of SWI/SNF complex activity in differentiating cells.
  • Chromatin immunoprecipitation to assess direct promoter targeting.
  • Gene expression analysis to quantify c-myc, p21(WAF1/CIP1), and E2F-responsive genes.

Main Results:

  • SWI/SNF-related complexes directly target the c-myc gene promoter to repress its expression in differentiating cells.
  • Repression of c-myc expression by SWI/SNF complexes is a prerequisite for the induction of p21(WAF1/CIP1).
  • Regulation of E2F-responsive genes by SWI/SNF complexes is independent of c-myc and p21(WAF1/CIP1) regulation.

Conclusions:

  • Mammalian SWI/SNF complexes control cell proliferation through a distinct pathway involving direct c-myc repression during differentiation.
  • The findings establish a novel mechanistic link where c-myc repression precedes p21(WAF1/CIP1) induction.
  • SWI/SNF-mediated regulation of c-myc and E2F pathways are partially separable, highlighting complex regulatory roles.

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