Molecular Cell
Volume 32, Issue 4, 21 November 2008, Pages 554-563
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Article
Inhibition of PAX3 by TGF-β Modulates Melanocyte Viability

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Summary

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-β/Smads. UV irradiation represses TGF-β in keratinocytes, and the repression of TGF-β/Smads upregulates PAX3 in melanocytes, which is associated with a UV-induced melanogenic response and consequent pigmentation. Furthermore, the TGF-β-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.

SIGNALING
CELLCYCLE

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Present address: Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200127, China