Document Detail


Runt-related transcription factor 1 (RUNX1) stimulates tumor suppressor p53 protein in response to DNA damage through complex formation and acetylation.
MedLine Citation:
PMID:  23148227     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Dan Wu; Toshinori Ozaki; Yukari Yoshihara; Natsumi Kubo; Akira Nakagawara
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-11-12
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  288     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-14     Completed Date:  2013-03-26     Revised Date:  2014-01-23    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1353-64     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
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:
0/Core Binding Factor Alpha 2 Subunit; 0/DNA Primers; 0/RUNX1 protein, human; 0/Tumor Suppressor Protein p53; 80168379AG/Doxorubicin
Comments/Corrections

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