Inhibition of PAX3 by TGF-beta modulates melanocyte viability.
The protein encoded by paired-box homeotic gene 3 (PAX3) is a key regulator of the microphthalmia-associated transcription factor (Mitf) in the melanocyte lineage. Here, we show that PAX3 expression in skin is directly inhibited by TGF-beta/Smads. UV irradiation represses TGF-beta in keratinocytes, and the repression of TGF-beta/Smads upregulates PAX3 in melanocytes, which is associated with a UV-induced melanogenic response and consequent pigmentation. Furthermore, the TGF-beta-PAX3 signaling pathway interacts with the p53-POMC/MSH-MC1R signaling pathway, and both are crucial in melanogenesis. The activation of p53-POMC/MSH-MC1R signaling is required for the UV-induced melanogenic response because PAX3 functions in synergy with SOX10 in a cAMP-response element (CRE)-dependent manner to regulate the transcription of Mitf. This study will provide a rich foundation for further research on skin cancer prevention by enabling us to identify targeted small molecules in the signaling pathways of the UV-induced melanogenic response that are highly likely to induce naturally protective pigmentation.
Yang
Guang
G
Department of Medical Oncology, Dana-Farber Cancer Institute, Children's Hospital Boston, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
Li
Yitang
Y
Nishimura
Emi K
EK
Xin
Hong
H
Zhou
Anyu
A
Guo
Yinshi
Y
Dong
Liang
L
Denning
Mitchell F
MF
Nickoloff
Brian J
BJ
Cui
Rutao
R
D005786:Gene Expression Regulation; D005809:Genes, Regulator; D017930:Genes, Reporter; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000528:radiation effects; D008156:Luciferases / Q000378:metabolism; D008544:Melanocytes / Q000378:metabolism / Q000502:physiology*; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D012880:Skin Pigmentation / Q000235:genetics / Q000502:physiology; D051901:Smad4 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays
D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; D008156:Luciferases