Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation.
Notch signaling promotes commitment of keratinocytes to differentiation and suppresses tumorigenesis. p63, a p53 family member, has been implicated in establishment of the keratinocyte cell fate and/or maintenance of epithelial self-renewal. Here we show that p63 expression is suppressed by Notch1 activation in both mouse and human keratinocytes through a mechanism independent of cell cycle withdrawal and requiring down-modulation of selected interferon-responsive genes, including IRF7 and/or IRF3. In turn, elevated p63 expression counteracts the ability of Notch1 to restrict growth and promote differentiation. p63 functions as a selective modulator of Notch1-dependent transcription and function, with the Hes-1 gene as one of its direct negative targets. Thus, a complex cross-talk between Notch and p63 is involved in the balance between keratinocyte self-renewal and differentiation.
Nguyen
Bach-Cuc
BC
Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA, and Department of Biochemistry, University of Lausanne, Switzerland.
Lefort
Karine
K
Mandinova
Anna
A
Antonini
Dario
D
Devgan
Vikram
V
Della Gatta
Giusy
G
Koster
Maranke I
MI
Zhang
Zhuo
Z
Wang
Jian
J
Tommasi di Vignano
Alice
A
Kitajewski
Jan
J
Chiorino
Giovanna
G
Roop
Dennis R
DR
Missero
Caterina
C
Dotto
G Paolo
GP
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000502:physiology*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology*; D051379:Mice; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering; D051881:Receptor, Notch1 / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D017931:DNA Primers; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins