CCAAT/enhancer Binding Protein-alpha (C/EBP-alpha) is a DNA-damage Inducible p53-regulated Mediator of the G1 Checkpoint.

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dc.contributor.advisor Robert C. Smart, Committee Chair en_US
dc.contributor.advisor Jun Ninomiya-Tsuji, Committee Member en_US
dc.contributor.advisor Yoshiaki Tsuji, Committee Member en_US
dc.contributor.advisor William K. Kaufmann, Committee Member en_US
dc.contributor.author Yoon, Kyungsil en_US
dc.date.accessioned 2010-04-02T18:44:11Z
dc.date.available 2010-04-02T18:44:11Z
dc.date.issued 2005-05-10 en_US
dc.identifier.other etd-05102004-135644 en_US
dc.identifier.uri http://www.lib.ncsu.edu/resolver/1840.16/4076
dc.description.abstract CCAAT/enhancer binding proteins (C/EBPs) are members of basic leucine zipper class of transcription factors, and C/EBPα is abundantly expressed in epidermal keratinocytes. C/EBPα has been shown to play an important role in cell cycle arrest and/or differentiation in various cell types, and forced expression of C/EBPα blocks keratinocyte proliferation suggesting a cell cycle regulatory function of C/EBPα in keratinocytes. Skin is constantly challenged by environmental stressors including sunlight, and there is a strong association between human skin cancers and exposure to UVB radiation. We report that UVB radiation is a potent inducer of C/EBPα in human and mouse keratinocytes as well as in mouse skin in vivo. UVB irradiation of keratinocytes resulted in the transcriptional upregulation of C/EBPα mRNA producing >70 fold increase in C/EBPα protein. Treatment of keratinocytes with other DNA damaging agents such as MNNG, etoposide and bleomycin also induced C/EBPα, suggesting that the induction of C/EBPα is a general DNA damage response in keratinocytes. The UVB-induction of C/EBPα was temporarily accompanied by UVB-induced p53 accumulation implying a possible relationship between these two proteins. Caffeine, an inhibitor of ATM and ATR kinases, inhibited UVB-induction of C/EBPα as well as p53 increase, and C/EBPα promoter was activated by p53 and UVB irradiation. Exposure of p53-deficient or mutant p53 containing keratinocytes to UVB failed to induce C/EBPα demonstrating that p53 is required for UVB-induction of C/EBPα. Enforced expression of C/EBPα in keratinocytes inhibited cell proliferation suggesting C/EBPα negatively regulates cell growth. UVB induced a more rapid growth arrest in keratinocytes overexpressing C/EBPα. Furthermore, UVB irradiation of C/EBPα knockdown keratinocytes displayed a greatly attenuated DNA damage G1 checkpoint and this was associated with increased sensitivity to UVB-induced apoptosis. Taken together, our results identify C/EBPα as a novel p53-regulated DNA damage-inducible gene that has a critical function in the DNA damage G1 checkpoint response in keratinocytes. en_US
dc.rights I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to NC State University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. en_US
dc.subject skin en_US
dc.subject DNA damage response en_US
dc.subject ultraviolet en_US
dc.subject keratinocytes en_US
dc.subject UVB en_US
dc.subject C/EBP en_US
dc.title CCAAT/enhancer Binding Protein-alpha (C/EBP-alpha) is a DNA-damage Inducible p53-regulated Mediator of the G1 Checkpoint. en_US
dc.degree.name PhD en_US
dc.degree.level dissertation en_US
dc.degree.discipline Toxicology en_US


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