MITF and UV responses in skin: From pigmentation to addiction

Ultraviolet radiation (UVR) has numerous effects on skin, including DNA damage, tanning, vitamin D synthesis, carcinogenesis, and immunomodulation. Keratinocytes containing damaged DNA secrete both alpha-melanocyte-stimulating hormone (alpha-MSH), which stimulates pigment production by melanocytes, and the opioid beta-endorphin, which can trigger addiction-like responses to UVR. The pigmentation (tanning) response is an adaptation that provides some delayed protection against further DNA damage and carcinogenesis, while the opioid response may be an evolutionary adaptation for promoting sun-seeking behavior to prevent vitamin D deficiency. Here, we review the pigmentation response to UVR, driven by melanocytic microphthalmia-associated transcription factor (MITF), and evidence for UVR-induced melanomagenesis and addiction. We also discuss potential applications of a novel approach to generate protective pigmentation in the absence of UVR (sunless tanning) using a topical small-molecule inhibitor of the salt-inducible kinase (SIK) family.