title: Loss of ARF sensitizes transgenic BRAFV600E mice to UV-induced melanoma via suppression of XPC.
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.
authors: Graduate Program in Genetics, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA.
authors: Chi
authors: C
authors: Luo
authors: Jinghao
authors: J
authors: Sheng
authors: Miaofen G
authors: MG
authors: Hu
authors: Frank G
authors: FG
authors: Haluska
authors: Rutao
authors: R
authors: Cui
authors: Zhengping
authors: Z
authors: Xu
authors: Philip N
authors: PN
authors: Tsichlis
authors: Guo-Fu
authors: GF
authors: Hu
authors: Philip W
authors: PW
authors: Hinds
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D019175:DNA Methylation; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D050704:E2F4 Transcription Factor / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D008546:Melanoma, Experimental / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D011401:Promoter Regions, Genetic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D050680:Transcription Factor DP1 / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014466:Ultraviolet Rays
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D050704:E2F4 Transcription Factor; C493763:E2f4 protein, mouse; C493736:Tfdp1 protein, mouse; D050680:Transcription Factor DP1; D016159:Tumor Suppressor Protein p53; C501002:Xpc protein, mouse; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf
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