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Induction of cyclin D1 transcription and CDK2 activity by Notch(ic): implication for cell cycle disruption in

C Ronchini1, A J Capobianco

  • 1Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0524, USA.

Molecular and Cellular Biology
|August 4, 2001
PubMed

Insights

Notch proteins can transform cells by directly activating cyclin D1 gene expression, leading to cell cycle deregulation and uncontrolled proliferation. This mechanism involves a CSL-dependent pathway, offering new insights into oncogenesis.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Notch genes encode transmembrane proteins crucial for cellular processes like differentiation and proliferation.
  • While Notch genes are known oncogenes, the precise mechanism of cellular transformation remains unclear.
  • Previous studies established inducible RKE cell transformation via hormone-activated Notch(ic)-estrogen receptor (ER) chimeras.

Purpose of the Study:

  • To elucidate the mechanism by which Notch proteins transform cells.
  • To investigate the direct targets of Notch intracellular domain (Notch(ic)) in cellular transformation.
  • To determine if Notch(ic) directly regulates cell cycle control factors.

Main Methods:

  • Utilized an inducible system with hormone-activated Notch(ic)-estrogen receptor (ER) chimeras.
  • Assessed the transcriptional activation of the cyclin D1 gene.
  • Measured CDK2 activity and S-phase entry.
  • Identified CSL binding sites in cyclin D1 promoters.

Main Results:

  • Notch(ic) rapidly activates cyclin D1 transcription independently of growth factors or secondary activators.
  • Hormone-activated Notch(ic)-ER induces CDK2 activity and promotes S-phase entry, even without serum.
  • Nontransforming Notch(ic) variants do not induce cyclin D1 expression.
  • A CSL binding site was identified in cyclin D1 promoters, suggesting a CSL-dependent activation pathway.

Conclusions:

  • Notch(ic) directly regulates cell cycle control factors, impacting cellular proliferation.
  • Cell cycle deregulation via constitutive cyclin D1 expression is a key mechanism of Notch-mediated transformation.
  • Notch(ic) likely activates cyclin D1 transcription through a CSL-dependent pathway.

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