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[摘要]：We observed that CCAAT/enhancer-binding protein (C/EBP)alpha is highly inducible in primary fibroblasts by DNA-damaging agents that induce strand breaks, alkylate and crosslink DNA as well as those that produce bulky DNA lesions. Fibroblasts deficient in C/EBP alpha (C/EBP alpha(-/-)) display an impaired G(1) checkpoint as evidenced by an inappropriate entry into the S-phase in response to DNA damage, and these cells also display an enhanced G(1)/S transition in response to mitogens. The induction of C/EBP alpha by DNA damage in fibroblasts does not require p53. Electrophoretic mobility shift assay (EMSA) analysis of nuclear extracts prepared from ultraviolet B (UVB)- and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-treated fibroblasts showed increased binding of C/EBP beta to a C/EBP consensus sequence and chromatin immunoprecipitation (ChIP) analysis also showed increased C/EBP beta binding to the C/EBP alpha promoter. To determine whether C/EBP beta has a function in the regulation of C/EBP alpha, we treated C/EBP beta(-/-) fibroblasts with UVB or MNNG. We observed that C/EBP alpha induction was impaired in both UVB- and MNNG-treated C/EBP beta(-/-) fibroblasts. Our study shows a novel function for C/EBP beta in the regulation of C/EBP alpha in response to DNA damage and provides definitive genetic evidence that C/EBP alpha has a critical role in the DNA damage G(1) checkpoint. Oncogene (2009) 28, 3235-3245; doi: 10.1038/onc.2009.176; published online 6 July 2009 |
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