Article
- The EMBO Journal (2008) 27, 1243 - 1254
- doi:10.1038/emboj.2008.45
Published online: 3 April 2008
Subject Categories:
The FoxO3a gene is a key negative target of canonical Notch signalling in the keratinocyte UVB response
Anna Mandinova1,5, Karine Lefort2,5, Alice Tommasi di Vignano1, Wesley Stonely1, Paola Ostano3, Giovanna Chiorino3, Haruhi Iwaki4, Jotaro Nakanishi4 and G Paolo Dotto1,2
- Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA, USA
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
- Laboratory of Cancer Pharmacogenomics, Fondo 'Edo Tempia', Biella, Italy
- Shiseido Life Science Research Center, Fukuura, Kanazawa-ku, Yokohama, Japan
Correspondence to:
G Paolo Dotto, Department of Biochemistry, University of Lausanne, Chemin de Boveresses 155, Epalinges 1066, Switzerland. Tel.: +41 21 692 5720; Fax: +41 21 692 5705; E-mail: Gian-Paolo.Dotto@unil.ch
5These authors contributed equally to this work
Received 4 July 2007; Accepted 17 December 2007
Abstract
Notch signalling has an important role in skin homeostasis, promoting keratinocyte differentiation and suppressing tumorigenesis. Here we show that this pathway also has an essential anti-apoptotic function in the keratinocyte UVB response. Notch1 expression and activity are significantly induced, in a p53-dependent manner, by UVB exposure of primary keratinocytes as well as intact epidermis of both mouse and human origin. The apoptotic response to UVB is increased by deletion of the Notch1 gene or down-modulation of Notch signalling by pharmacological inhibition or genetic suppression of 'canonical' Notch/CSL/MAML1-dependent transcription. Conversely, Notch activation protects keratinocytes against apoptosis through a mechanism that is not linked to Notch-induced cell cycle withdrawal or NF-
B activation. Rather, transcription of FoxO3a, a key pro-apoptotic gene, is under direct negative control of Notch/HERP transcription in keratinocytes, and upregulation of this gene accounts for the increased susceptibility to UVB of cells with suppressed Notch signalling. Thus, the canonical Notch/HERP pathway functions as a protective anti-apoptotic mechanism in keratinocytes through negative control of FoxO3a expression.
Keywords:
- apoptosis,
- FoxO3a,
- Notch,
- p53,
- UVB
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