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• W2037615521 abstract "DNA damage activates cell cycle checkpoints to promote cell cycle arrest. p53 is a major player in checkpoints by activating expression of the cdk inhibitor p21 and repressing expression of cyclin B. DNA damage-induced S and G2 arrest following treatment with the topoisomerase I inhibitor SN38 is abrogated in p53-defective cells by treatment with the Chk1 inhibitor 7-hydroxystaurosporine (UCN-01). Previously, we compared p53 wildtype MCF10A cells with derivatives whose p53 function is inhibited by overexpression of the tetramerization domain (MCF10A/OD) or overexpression of shRNA against p53 (MCF10A/αp53) (Levesque et al, Oncogene 24, 3786, 2005). Treatment of MCF10A/OD with SN38 followed by UCN-01 results in abrogation of S, but not G2, arrest, while the MCF10A/αp53 abrogated both S and G2 arrest. The S abrogation correlated with reduced p21, consistent with the requirement of p53 tetramerization for activation of p21 expression. Failure of G2 abrogation correlated with reduced cyclin B, suggesting that tetramerization of p53 is not required for repression of cyclin B expression. In the present study, we confirmed that the p53-dependent repression of cyclin B in response to DNA damage occurs at the transcriptional level by analyzing cyclin B mRNA levels. Treatment of MCF10A and MCF10A/OD with SN38 resulted in reduction of cyclin B mRNA levels whereas treatment of MCF10A/αp53 with SN38 did not. This reflects the change in protein levels following SN38 treatment. We next analyzed p53 oligomerization using glutaraldehyde crosslinking. Following SN38 treatment, MCF10A contained oligomeric forms of p53 with molecular weights approximating monomers, dimers, trimers, and tetramers. MCF10A/OD, however, possessed monomers and dimers, but lacked trimers and tetramers. These results suggest that p53 monomers or dimers are involved in repression of cyclin B. One model to explain the p53-mediated repression of cyclin B in MCF10A/OD is that p53 dimers, rather than tetramers, bind to a p53 response element in the cyclin B promoter. While genes transcriptionally activated by p53 contain a consensus sequence with elements repeated in a head-to-tail orientation, the cyclin B promoter contains similar elements oriented head-to-head. We performed both chromatin immunoprecipitation (ChIP) assays and electrophoretic mobility shift assays (EMSA) to determine whether p53 binds to this head-to-head element. ChIP assays revealed that p53 associates with this element in MCF10A and MCF10A/OD but not in MCF10A/αp53. We performed EMSA using a biotin-labeled probe containing the head-to-head element and observed shifts in mobility consistent with the molecular weight of tetramers and dimers using MCF10A nuclear extract (NE), but observed only the dimeric shift with MCF10A/OD NE, and no shift with MCF10A/αp53 NE. Taken together, these results suggest p53 dimers associate with the head-to-head element to repress cyclin B transcription. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2220. doi:1538-7445.AM2012-2220" @default.
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• W2037615521 date "2012-04-15" @default.
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• W2037615521 title "Abstract 2220: p53 dimers associate with a head-to-head element to repress cyclin B transcription" @default.
• W2037615521 doi "https://doi.org/10.1158/1538-7445.am2012-2220" @default.
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