Post-Grant Reports

Title

Investigation of Skin Cancer-associated Melanocortin-1 Receptor Gene Variants

Document Type

Report

Publication Date

2-14-2021

Disciplines

Cancer Biology | Cell Biology | Skin and Connective Tissue Diseases

Abstract

Skin cancer is the most prevalent cancer in the United States, affecting one in five Americans, killing approximately 12,000 people annually. The goal of this project is to research the known skin cancer gene, the melanocortin-1 receptor (MC1R). While improper MC1R function can lead to skin cancer in all individuals, a subset of MC1R genetic variants are associated with increased skin cancer risk, independent of sun exposure. Ultraviolet radiation (UVR) from the sun activates melanocortin signaling pathways in skin pigment cells, called melanocytes, to produce brown/black eumelanin pigments. Eumelanin protects skin cell DNA from UVR and is produced by normally functioning melanocytes through activation of the melanocortin-1 receptor (MC1R) by melanocyte stimulating hormone. In addition to melanin synthesis, MC1R signaling promotes the transfer of melanin to skin cell keratinocytes to protect skin DNA from UVR damage, which can cause cancerous mutations. Inhibition of MC1R signaling prevents eumelanin production and results in red/yellow pheomelanin production instead. Pheomelanin is not photoprotective, and individuals who produce predominately pheomelanin are at greater risk for developing melanoma skin cancer. Two of the most frequent melanoma-associated MC1R variants are MC1R-R151C and MC1R-D294H. How these genetic variants alter MC1R function in physiologically relevant melanocytes is not well understood. Our data suggest that MC1R- R151C decreases the amount of MC1R expressed at the surface of melanocytes, while MC1R-D294H increases MC1R surface levels. Future work will investigate how the altered localization of these MC1R skin cancer-associated genetic variants affects MC1R signaling in response to UVR.

Comments

This research was conducted as part of a Linfield University Student-Faculty Collaborative Research Grant in 2020, funded by the Office of Academic Affairs.

The student collaborator was Whitney Wells.

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