Journal
EMBO JOURNAL
Volume 20, Issue 13, Pages 3427-3436Publisher
WILEY
DOI: 10.1093/emboj/20.13.3427
Keywords
cell cycle; integrins; keratins; p21(WAF1/Cip1); RBP-J kappa-CBF-1
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Funding
- NCI NIH HHS [CA73796, R01 CA073796, CA16038, P01 CA016038] Funding Source: Medline
- NIAMS NIH HHS [R01 AR039190, AR39190] Funding Source: Medline
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The role of Notch signaling in growth/differentiation control of mammalian epithelial cells is still poorly defined. We show that keratinocyte-specific deletion of the Notch1 gene results in marked epidermal hyperplasia and deregulated expression of multiple differentiation markers. In differentiating primary keratinocytes in vitro endogenous Notch1 is required for induction of p21(WAF1/Cip1) expression, and activated Notch1 causes growth suppression by inducing p21(WAF1/Cip1) expression. Activated Notch1 also induces expression of 'early' differentiation markers, while suppressing the late markers. Induction of p21(WAF1/Cip1) expression and early differentiation markers occur through two different mechanisms, The RBP-JK protein binds directly to the endogenous p21 promoter and p21 expression is induced specifically by activated Notch1 through RBP-J kappa -dependent transcription. Expression of early differentiation markers is RBP-J kappa -independent and can be induced by both activated Notch1 and Notch2, as well as the highly conserved ankyrin repeat domain of the Notch1 cytoplasmic region. Thus, Notch signaling triggers two distinct pathways leading to keratinocyte growth arrest and differentiation.
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