The primary cause of skin cancer is chronic exposure to ultraviolet (UV) rays from sunlight. A crucial event in the prevention of UV-induced skin cancer is the repair of DNA damage and / or the removal of the damaged cell through apoptotic mechanisms. Failure to properly repair UV-induced DNA damage or remove the DNA damage in the cells through apoptosis may result in mutations, which can lead to skin cancer after clonal expansion of these mutated cells. Since UV preferentially mutates the p53 tumor suppressor gene, which leads to skin cancer, and more than 50% of all human cancers have mutated p53, the regulation of genes involved in DNA repair and apoptosis by p53 are essential for maintaining genomic integrity. Recently, E2F1 has been shown to play a role in the response to DNA damage. Like, p53, E2F1 is phosphorylated and stabilized following UV irradiation and treatment with other agents that damage DNA. This is highly significant since the deregulation of E2F1 through the inactivation of the Rb tumor suppressor either through the mutation of the RB1 gene or the deregulation of cyclin D-associated kinase activity, is a thought to be a critical event the development of many human cancers. The mechanism by which E2F1 affects the UV-induced DNA-damage response pathway is unknown. The goal of this Mentored Career Development Award is to determine how E2F1 regulates DNA repair, apoptosis, and mutagenesis in response to UVB radiation and how this affects UVB-induced epidermal carcinogenesis.
Specific Aim 1 is to determine how E2F1 activity regulates the expression of DNA repair and apoptotic genes in response to UVB radiation.
Specific Aim 2 will determine the extent to which UVB-induced mutagenesis is affected by E2F1 activity. Finally, Specific Aim 3 will determine the role of E2F1 on UVB-induced carcinogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01CA106603-05
Application #
7637980
Study Section
Subcommittee G - Education (NCI)
Program Officer
Ojeifo, John O
Project Start
2005-05-03
Project End
2010-10-30
Budget Start
2009-05-01
Budget End
2010-10-30
Support Year
5
Fiscal Year
2009
Total Cost
$139,847
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
Organized Research Units
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Guo, Ruifeng; Chen, Jie; Zhu, Feng et al. (2010) E2F1 localizes to sites of UV-induced DNA damage to enhance nucleotide excision repair. J Biol Chem 285:19308-15