The FoxO3a gene is a key negative target of canonical Notch signalling in the keratinocyte UVB response.
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.
Mandinova
Anna
A
Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA, USA.
Lefort
Karine
K
Tommasi di Vignano
Alice
A
Stonely
Wesley
W
Ostano
Paola
P
Chiorino
Giovanna
G
Iwaki
Haruhi
H
Nakanishi
Jotaro
J
Dotto
G Paolo
GP
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000528:radiation effects*; D051379:Mice; D051881:Receptor, Notch1 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology* / Q000528:radiation effects*; D012867:Skin / Q000166:cytology / Q000528:radiation effects; D014466:Ultraviolet Rays
D051017:Apoptosis Regulatory Proteins; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D051881:Receptor, Notch1