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p21WAF1/Cip1 is a negative transcriptional regulator of Wnt4 expression downstream of Notch1 activation

Vikram Devgan1, Cristina Mammucari, Sarah E Millar

  • 1Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.

Genes & Development
|June 21, 2005
PubMed

Insights

Notch1 activation suppresses Wnt signaling in keratinocytes via p21(WAF1/Cip1), a cell cycle-independent regulator. This study reveals p21 selectively down-regulates Wnt4 gene expression, linking Notch and Wnt pathways in skin cell growth.

Area of Science:

  • Cellular biology
  • Molecular biology
  • Dermatology

Background:

  • Notch1 signaling is a tumor suppressor in keratinocytes, linked to Wnt pathway down-regulation.
  • p21(WAF1/Cip1), a cyclin-dependent kinase inhibitor, is a direct target of Notch1 activation.

Purpose of the Study:

  • To elucidate the mechanism by which Notch1 activation suppresses Wnt signaling.
  • To investigate the role of p21 in mediating Notch1's effect on Wnt gene expression.
  • To understand the link between Notch and Wnt pathways in keratinocyte proliferation and tumor development.

Main Methods:

  • Analysis of gene expression in keratinocytes.
  • Investigation of protein-DNA interactions at the Wnt4 promoter.
  • Assessment of histone acetylation and transcription factor recruitment.

Main Results:

  • Notch1 activation suppresses Wnt signaling primarily through down-modulation of Wnt gene expression.
  • p21(WAF1/Cip1) acts as a negative regulator of Wnt transcription, independent of cell cycle effects.
  • p21 directly associates with E2F-1 at the Wnt4 promoter, reducing c-Myc and p300 recruitment and causing histone hypoacetylation.

Conclusions:

  • p21(WAF1/Cip1) selectively inhibits Wnt4 gene transcription.
  • This mechanism establishes a functional link between the Notch and Wnt signaling pathways.
  • The Notch1-p21 axis plays a crucial role in controlling keratinocyte growth and preventing tumor development.

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