Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation
- Bach-Cuc Nguyen1,
- Karine Lefort2,
- Anna Mandinova1,
- Dario Antonini3,
- Vikram Devgan1,
- Giusy Della Gatta3,
- Maranke I. Koster4,
- Zhuo Zhang1,
- Jian Wang1,
- Alice Tommasi di Vignano1,
- Jan Kitajewski5,
- Giovanna Chiorino6,
- Dennis R. Roop4,
- Caterina Missero3,7,9, and
- G. Paolo Dotto1,2,7,8
- 1 Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA;
- 2 Department of Biochemistry, University of Lausanne, Epalinges 1066 CH, Switzerland;
- 3 Telethon Institute of Genetics and Medicine (TIGEM), 80131 Naples, Italy;
- 4 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA;
- 5 Department of Pathology, Department of Obstetrics and Gynecology, and Irving Cancer Research Center, Columbia University Medical Center, New York, New York 10032, USA;
- 6 Laboratory of Cancer Pharmacogenomics, Fondo “Edo Tempia,” 13900 Biella, Italy
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↵7 These authors contributed equally to this work.
Abstract
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.
Keywords
Footnotes
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↵8 Corresponding authors.
↵8 E-MAIL gdotto{at}partners.org; FAX 41-21-692-5705.
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↵9 E-MAIL missero{at}tigem.it; FAX 39-081-6132351.
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Supplemental material is available at http://www.genesdev.org.
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Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1406006
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- Received December 27, 2005.
- Accepted February 10, 2006.
- Copyright © 2006, Cold Spring Harbor Laboratory Press
