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Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation
Author(s) -
Rangarajan Annapoorni,
Talora Claudio,
Okuyama Ryuhei,
Nicolas Michael,
Mammucari Cristina,
Oh Heysun,
Aster Jon C.,
Krishna Sudhir,
Metzger Daniel,
Chambon Pierre,
Miele Lucio,
Aguet Michel,
Radtke Freddy,
Dotto G.Paolo
Publication year - 2001
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/20.13.3427
Subject(s) - biology , notch signaling pathway , microbiology and biotechnology , keratinocyte , cellular differentiation , transcription factor , signal transduction , cell culture , genetics , gene
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‐Jκ protein binds directly to the endogenous p21 promoter and p21 expression is induced specifically by activated Notch1 through RBP‐Jκ‐dependent transcription. Expression of early differentiation markers is RBP‐Jκ‐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.