Journal
CELL DEATH AND DIFFERENTIATION
Volume 15, Issue 11, Pages 1734-1744Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2008.105
Keywords
apoptosis; p53; C/EBP beta; p19(Arf); DNA damage; keratinocytes
Categories
Funding
- National Cancer Institute [CA046637]
- National Institute of Environmental Health Sciences [ES012473]
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CCAAT/enhancer-binding protein-beta (C/EBP beta) is a mediator of cell survival and tumorigenesis. When C/EBP beta(-/-) mice are treated with carcinogens that produce oncogenic Ras mutations in keratinocytes, they respond with abnormally elevated keratinocyte apoptosis and a block in skin tumorigenesis. Although this aberrant carcinogen-induced apoptosis results from abnormal upregulation of p53, it is not known whether upregulated p53 results from oncogenic Ras and its ability to induce p19(Arf) and/or activate DNA-damage response pathways or from direct carcinogen-induced DNA damage. We report that p19(Arf) is dramatically elevated in C/EBP beta(-/-) epidermis and that C/EBP beta represses a p19(Arf) promoter reporter. To determine whether p19(Arf) is responsible for the proapoptotic phenotype in C/EBP beta(-/-) mice, C/EBP beta(-/-); p19(Arf-/-) mice were generated. C/EBP beta(-/-); p19(Arf-/-) mice responded to carcinogen treatment with increased p53 and apoptosis, indicating p19(Arf) is not essential. To ascertain whether oncogenic Ras activation induces aberrant p53 and apoptosis in C/EBP beta(-/-) epidermis, we generated K14-ER: Ras; C/EBP beta(-/-) mice. Oncogenic Ras activation induced by 4-hydroxytamoxifen did not produce increased p53 or apoptosis. Finally, when C/EBP beta(-/-) mice were treated with differing types of DNA-damaging agents, including alkylating chemotherapeutic agents, they displayed aberrant levels of p53 and apoptosis. These results indicate that C/EBP beta represses p53 to promote cell survival downstream of DNA damage and suggest that inhibition of C/EBP beta may be a target for cancer cotherapy to increase the efficacy of alkylating chemotherapeutic agents.
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