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Loss of ARF sensitizes transgenic BRAFV600E mice to UV-induced melanoma via suppression of XPC.

Authors
  • Luo, Chi
  • Sheng, Jinghao
  • Hu, Miaofen G
  • Haluska, Frank G
  • Cui, Rutao
  • Xu, Zhengping
  • Tsichlis, Philip N
  • Hu, Guo-Fu
  • Hinds, Philip W
Type
Published Article
Journal
Cancer Research
Publisher
American Association for Cancer Research
Publication Date
Jul 15, 2013
Volume
73
Issue
14
Pages
4337–4348
Identifiers
DOI: 10.1158/0008-5472.CAN-12-4454
PMID: 23650282
Source
Medline
License
Unknown

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.

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