Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation

BC Nguyen, K Lefort, A Mandinova… - Genes & …, 2006 - genesdev.cshlp.org
BC Nguyen, K Lefort, A Mandinova, D Antonini, V Devgan, G Della Gatta, MI Koster, Z Zhang
Genes & development, 2006genesdev.cshlp.org
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 …
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.
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