Ultraviolet irradiation represses PATCHED gene transcription in human epidermal keratinocytes through an activator protein-1-dependent process.
Basal cell carcinoma (BCC) is one of the major types of skin cancer arising from keratinocytes. The SONIC HEDGEHOG pathway is deregulated in 100% of sporadic BCCs, as indicated by the overexpression of PATCHED, whose product encodes the receptor of SONIC HEDGEHOG, in 100% of analyzed BCCs. Reverse transcription-PCR analysis revealed that exposure to UVB irradiation, which is a risk factor known to contribute to BCC development, induces a strong and sharp decrease of PATCHED mRNA level both in vitro and ex vivo. Transcription of a reporter gene driven by the 4.4-kb 5'-regulatory region of the human PATCHED gene was shown to be down-regulated after UVB irradiation. Furthermore, overexpression of c-JUN, a member of the activator protein (AP)-1 family, induced repression of the PATCHED promoter. The role of AP-1 in UVB-induced PATCHED repression was confirmed in mouse embryonic fibroblasts knocked out for c-JUN NH(2)-terminal protein kinase. This study thus provides the first evidence of UV-induced down-regulation at the transcriptional level of the BCC-associated tumor suppressor PATCHED relying on activation of the AP-1 oncogenic pathway.
Brellier
Florence
F
Laboratory of Genetic Instability and Cancer, Centre National de la Recherche Scientifique UPR2169, Institut Gustave Roussy, Villejuif Cedex, France.
Marionnet
Claire
C
Chevallier-Lagente
Odile
O
Toftgard
Rune
R
Mauviel
Alain
A
Sarasin
Alain
A
Magnaldo
Thierry
T
D000328:Adult; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D002675:Child, Preschool; D004307:Dose-Response Relationship, Radiation; D000078404:Epidermal Cells; D004817:Epidermis / Q000502:physiology / Q000528:radiation effects; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000502:physiology* / Q000528:radiation effects*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000528:radiation effects; D000072079:Patched Receptors; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011956:Receptors, Cell Surface; D018808:Transcription Factor AP-1 / Q000502:physiology / Q000528:radiation effects*; D014158:Transcription, Genetic / Q000528:radiation effects; D015533:Transcriptional Activation / Q000528:radiation effects*
D008565:Membrane Proteins; D000072079:Patched Receptors; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D018808:Transcription Factor AP-1