Abstract
Both genetic mutations and UV irradiation (UVR) can predispose individuals to melanoma. Although BRAF(V600E) is the most prevalent oncogene in melanoma, the BRAF(V600E) mutant is not sufficient to induce tumors in vivo. Mutation at the CDKN2A locus is another melanoma-predisposing event that can disrupt the function of both p16(INK4a) and ARF. Numerous studies have focused on the role of p16(INK4a) in melanoma, but the involvement of ARF, a well-known p53 activator, is still controversial. Using a transgenic BRAF(V600E) mouse model previously generated in our laboratory, we report that loss of ARF is able to enhance spontaneous melanoma formation and cause profound sensitivity to neonatal UVB exposure. Mechanistically, BRAF(V600E) and ARF deletion synergize to inhibit nucleotide excision repair by epigenetically repressing XPC and inhibiting the E2F4/DP1 complex. We suggest that the deletion of ARF promotes melanomagenesis not by abrogating p53 activation but by acting in concert with BRAF(V600E) to increase the load of DNA damage caused by UVR.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
