| Runt-related transcription factor 1 (RUNX1) stimulates tumor suppressor p53 protein in response to DNA damage through complex formation and acetylation. | |
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MedLine Citation:
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PMID: 23148227 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Representative tumor suppressor p53 plays a critical role in the regulation of proper DNA damage response. In this study, we have found for the first time that Runt-related transcription factor 1 (RUNX1) contributes to p53-dependent DNA damage response. Upon adriamycin (ADR) exposure, p53 as well as RUNX1 were strongly induced in p53-proficient HCT116 and U2OS cells, which were closely associated with significant transactivation of p53 target genes, such as p21(WAF)(1), BAX, NOXA, and PUMA. RUNX1 was exclusively expressed in the cell nucleus and formed a complex with p53 in response to ADR. Chromatin immunoprecipitation assay demonstrated that p53 together with RUNX1 are efficiently recruited onto p53 target gene promoters following ADR exposure, indicating that RUNX1 is involved in p53-mediated transcriptional regulation. Indeed, forced expression of RUNX1 stimulated the transcriptional activity of p53 in response to ADR. Consistent with these observations, knockdown of RUNX1 attenuated ADR-mediated induction of p53 target genes and suppressed ADR-dependent apoptosis. Furthermore, RUNX1 was associated with p300 histone acetyltransferase, and ADR-dependent acetylation of p53 at Lys-373/382 was markedly inhibited in RUNX1 knockdown cells. In addition, knockdown of RUNX1 resulted in a significant decrease in the amount of p53-p300 complex following ADR exposure. Taken together, our present results strongly suggest that RUNX1 is required for the stimulation of p53 in response to DNA damage and also provide novel insight into understanding the molecular mechanisms behind p53-dependent DNA damage response. |
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Authors:
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Dan Wu; Toshinori Ozaki; Yukari Yoshihara; Natsumi Kubo; Akira Nakagawara |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2012-11-12 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 288 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-01-14 Completed Date: 2013-03-26 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 1353-64 Citation Subset: IM |
Affiliation:
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Laboratory of Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, 666-2 Nitona, Chiba 260-8717, Japan. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acetylation Base Sequence Blotting, Western Cell Line, Tumor Chromatin Immunoprecipitation Core Binding Factor Alpha 2 Subunit / genetics, physiology* DNA Damage* DNA Primers Doxorubicin / pharmacology Gene Knockdown Techniques Humans Promoter Regions, Genetic Reverse Transcriptase Polymerase Chain Reaction Transcription, Genetic Tumor Suppressor Protein p53 / genetics, physiology* |
| Chemical | |
Reg. No./Substance:
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0/Core Binding Factor Alpha 2 Subunit; 0/DNA Primers; 0/RUNX1 protein, human; 0/Tumor Suppressor Protein p53; 23214-92-8/Doxorubicin |
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