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Loss of ARF sensitizes transgenic BRAFV600E mice to UV-induced melanoma via suppression of XPC
- Publication Year :
- 2013
-
Abstract
- Both genetic mutations and UV irradiation (UVR) can predispose individuals to melanoma. Although BRAFV600E is the most prevalent oncogene in melanoma, the BRAFV600E 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 p16INK4a and ARF. Numerous studies have focused on the role of p16INK4a in melanoma, but the involvement of ARF, a well-known p53 activator, is still controversial. Using a transgenic BRAFV600E 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, BRAFV600E 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 BRAFV600E to increase the load of DNA damage caused by UVR. Cancer Res; 73(14); 4337–48. ©2013 AACR.
- Subjects :
- Proto-Oncogene Proteins B-raf
Cancer Research
Neoplasms, Radiation-Induced
DNA Repair
DNA repair
DNA damage
Ultraviolet Rays
Transgene
Melanoma, Experimental
Mice, Transgenic
E2F4 Transcription Factor
Biology
Article
Mice
CDKN2A
Cell Line, Tumor
medicine
Animals
Humans
Promoter Regions, Genetic
E2F4
neoplasms
Melanoma
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p16
Mice, Knockout
Oncogene
DNA Methylation
medicine.disease
DNA-Binding Proteins
Mice, Inbred C57BL
Oncology
Cancer research
Tumor Suppressor Protein p53
Transcription Factor DP1
Nucleotide excision repair
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....7cde8e3106e54e0abc6072a8c57ec87a