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The activated Notch1 receptor cooperates with alpha-enolase and MBP-1 in modulating c-myc activity

Kai-Wen Hsu1, Rong-Hong Hsieh, Yan-Hwa Wu Lee

  • 1Department of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, 155, Sec. 2, Li-Nong St., Taipei 112, Taiwan.

Molecular and Cellular Biology
|May 21, 2008
PubMed

Insights

The activated Notch1 receptor (N1IC) and proteins alpha-enolase or MBP-1 control c-myc expression. They bind the c-myc promoter

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • The Notch signaling pathway influences tumorigenesis by promoting or suppressing cancer.
  • Activated Notch1 receptor intracellular domain (N1IC) upregulates the c-myc proto-oncogene.
  • N1IC and transcription factor YY1 bind the c-myc promoter, enhancing its expression independently of CBF1.

Purpose of the Study:

  • To investigate the interaction between N1IC and c-Myc-regulating proteins.
  • To elucidate the mechanism by which alpha-enolase and MBP-1 modulate N1IC-enhanced c-myc promoter activity.
  • To determine the role of these interactions in cellular processes like differentiation and colony formation.

Main Methods:

  • Co-immunoprecipitation to assess protein interactions.
  • Luciferase reporter assays to measure promoter activity.
  • Site-directed mutagenesis to identify key DNA response elements.
  • Cell culture experiments (K562 cells) to study differentiation and colony formation.

Main Results:

  • N1IC interacts with alpha-enolase and MBP-1, which suppress N1IC-enhanced c-myc promoter activity independently of CBF1.
  • The YY1 response element on the P2 c-myc promoter is crucial for modulation by N1IC, alpha-enolase, and MBP-1.
  • N1IC, YY1, alpha-enolase, and MBP-1 bind the c-myc promoter via the YY1 response element.
  • N1IC suppresses hemin-induced erythroid differentiation in K562 cells, an effect reversed by alpha-enolase and MBP-1.
  • Alpha-enolase and MBP-1 inhibit N1IC-driven colony formation by downregulating c-myc.

Conclusions:

  • Activated Notch1 receptor and alpha-enolase/MBP-1 cooperate to regulate c-myc expression.
  • This regulation occurs through binding to the YY1 response element of the c-myc promoter.
  • These findings provide insights into the molecular mechanisms underlying Notch signaling in tumorigenesis and cellular differentiation.

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