UV signaling pathways within the skin

Abstract

The effects of UVR on the skin include tanning, carcinogenesis, immunomodulation, and synthesis of vitamin D, among others. Melanocortin 1 receptor polymorphisms correlate with skin pigmentation, UV sensitivity, and skin cancer risk. This article reviews pathways through which UVR induces cutaneous stress and the pigmentation response. Modulators of the UV-tanning pathway include sunscreen agents, melanocortin 1 receptor activators, adenylate cyclase activators, phosphodiesterase 4D3 inhibitors, T-oligos, and microphthalmia-associated transcription factor regulators such as histone deacetylase inhibitors. UVR, as one of the most ubiquitous carcinogens, represents both a challenge and an enormous opportunity in skin cancer prevention.

Figure 1. The epidermal melanin unit and tanning response to UV radiation

UV radiation induces DNA damage, which leads to activation of p53. In turn, p53 stimulates transcriptional upregulation of the proopiomelanocortin (POMC) gene, which is post-translationally processed to adrenocorticotrophic hormone (ACTH), α-melanocyte-stimulating hormone (MSH), and β-endorphin. Secreted α-MSH binds to the melanocortin 1 receptor (MC1R) on melanocytes, leading to production of melanin. The melanin is packaged within melanosomes and transported back to keratinocytes, where they localize over the nucleus as part of the protective tanning response to UV radiation.

Figure 2. Melanin synthesis and strategies to regulate the tanning response

Secreted α-MSH from keratinocytes binds MC1R on melanocytes, leading to upregulation of cAMP, which stimulates expression of MITF. MITF then transcriptionally activates expression of enzymatic machinery including tyrosinase and tyrosinase-related protein 1 (Tyrp1), which are critical in the synthesis of melanin within melanosomes. Tyrosinase catalyzes the initial conversion of tyrosine to DOPA and dopaquinone. Dopaquinone may then combine with cysteine to form the pheomelanin precursor cysteinyldopa, or it may enter a separate pathway catalyzed in part by Tyrp1 to produce the eumelanin precursor. The matured melanin is then transported in vesicles called melanosomes to the overlying epidermal keratinocytes. Strategies such as MC1R activators, adenylate cyclase activators, Phosphodiesterase 4D3 inhibitors, and MITF regulators are shown to regulate the UV tanning response by targeting different components of this pathway.