Virtually presented via BlueJeans
Time: 10:00 – 11:00 am
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CE Credits: 1.0 lecture credits
Dr. Rutao Cui and his group provided a key insight into why red-haired people are more likely to get melanoma and found new preventative strategies for melanoma, especially in redheads. The melanocortin-1 receptor (MC1R), a G-protein-coupled receptor, has a crucial role in human and mouse pigmentation. Activation of MC1R in melanocytes by α-melanocyte-stimulating hormone (α-MSH) stimulates cAMP signaling and melanin production and enhances DNA repair after ultraviolet irradiation. Individuals carrying MC1R variants, especially those associated with red hair color, fair skin and poor tanning ability (denoted as RHC variants), are associated with higher risk of melanoma.
They introduced MC1R loss-of-function mutations into albino mice with complete absence of melanin, and found that MC1R loss-of-function mutations augment UV- induced melanoma development, independent of their effects on pigmentation. For the additional roles of MC1R in melanoma development beyond pigmentation, the group reported that MC1R controls UVB-induced G1- like cell cycle arrest and subsequent onset of premature senescence in melanocytes, abrogation of which contributes to melanoma development. Mechanistically, the group demonstrated that WT-MC1R stabilized PTEN against proteolytic degradation under UV exposure, resulting in inhibition of AKT phosphorylation and activation after UV exposure. These results provided a key insight into why red-haired people are more likely to get melanoma (Molecular Cell, 2013).
Dr. Rutao Cui and his group also found melanomas and for somatic C>T mutations, a signature linked to sun exposure, the expected single-nucleotide variant of MC1R count associated with the presence of a disruptive MC1R variants (R allele) is significantly higher than that among persons without an R allele (Nature Communication, 2016). Recently, they demonstrated a potential MC1R-targeted intervention strategy in mice to rescue loss-of-function MC1R in MC1R RHC variants for therapeutic benefit by activating MC1R protein palmitoylation. MC1R palmitoylation, primarily mediated by the protein-acyl transferase ZDHHC13, is essential for activating MC1R signaling, which triggers increased pigmentation, ultraviolet-B-induced G1-like cell cycle arrest and control of senescence and melanomagenesis in vitro and in vivo. Using C57BL/6J-Mc1re/eJ mice, in which endogenous MC1R is prematurely terminated, expressing Mc1r RHC variants, the group shows that pharmacological activation of palmitoylation rescues the defects of Mc1r RHC variants and prevents melanomagenesis (Nature, 2017 & Nature Communications, 2019).
Dr. Rutao Cui is a Professor and Vice Chair of Pharmacology and Experimental Therapeutics. He recieved his MD in 1994 from Shandong University of TCM, Jinan, China and his PhD in 2000 from Shanghai University of TCM, Shanghai, China. He continued with postdoctoral training as a Research Fellow for the Dana Farber Cancer Institute, Harvard Medical School, Boston, MA until 2007. From 2007-2009 he worked as an Assistant Professor of Pathology at Loyola University, Chicago, and later worked as an Associate Professor of Dermatology and Biochemistry at Boston University School of Medicine, MA from 2010-2015.
Disclosure: Dr. Cui has no relevant financial relationships to disclose.
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University of Pennsylvania School of Dental Medicine designates this activity for 1.0 continuing education credits.