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Molecular and Cellular Biology, December 2004, p. 10650-10660, Vol. 24, No. 24
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.24.10650-10660.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

C/EBP Is a DNA Damage-Inducible p53-Regulated Mediator of the G₁ Checkpoint in Keratinocytes

Cell Signaling and Cancer Group, Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina

Received 3 May 2004/ Returned for modification 25 May 2004/ Accepted 17 September 2004

The basic leucine zipper transcription factor, CCAAT/enhancer binding protein (C/EBP), is abundantly expressed in keratinocytes of the skin; however, its function in skin is poorly characterized. UVB radiation is responsible for the majority of human skin cancers. In response to UVB-induced DNA damage, keratinocytes activate cell cycle checkpoints that arrest cell cycle progression and prevent replication of damaged DNA, allowing time for DNA repair. We report here that UVB radiation is a potent inducer of C/EBP in human and mouse keratinocytes, as well as in mouse skin in vivo. UVB irradiation of keratinocytes resulted in the transcriptional up-regulation of C/EBP mRNA, producing a >70-fold increase in C/EBP protein levels. N-Methyl-N'-nitro-N-nitrosoguanidine, etoposide, and bleomycin also induced C/EBP. UVB-induced C/EBP was accompanied by an increase in p53 protein and caffeine, an inhibitor of ataxia-telangiectasia-mutated kinase, and ataxia-telangiectasia-mutated and Rad3-related kinase inhibited UVB-induced increases in both C/EBP and p53. UVB irradiation of p53-null or mutant p53-containing keratinocytes failed to induce C/EBP. UVB irradiation of C/EBP knockdown keratinocytes displayed a greatly diminished DNA damage G₁ checkpoint, and this was associated with increased sensitivity to UVB-induced apoptosis. Our results uncover a novel role for C/EBP as a p53-regulated DNA damage-inducible gene that has a critical function in the DNA damage G₁ checkpoint response in keratinocytes.

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