The FoxO3a gene is a key negative target of canonical Notch signalling in the keratinocyte UVB response.

Details

Serval ID
serval:BIB_D6DA77D24349
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
The FoxO3a gene is a key negative target of canonical Notch signalling in the keratinocyte UVB response.
Journal
EMBO journal
Author(s)
Mandinova A., Lefort K., Tommasi di Vignano A., Stonely W., Ostano P., Chiorino G., Iwaki H., Nakanishi J., Dotto G.P.
ISSN
1460-2075[electronic]
Publication state
Published
Issued date
2008
Volume
27
Number
8
Pages
1243-1254
Language
english
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-kappaB 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
Animals, Apoptosis Regulatory Proteins, Cell Line, Tumor, Cells, Cultured, Forkhead Transcription Factors, Gene Expression Regulation, Neoplastic, Hela Cells, Humans, Keratinocytes, Mice, Receptor, Notch1, Signal Transduction, Skin, Ultraviolet Rays
Pubmed
Web of science
Create date
24/03/2009 15:08
Last modification date
20/08/2019 15:56
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