Runt-related Transcription Factor 1 (RUNX1) Stimulates Tumor Suppressor p53 Protein in Response to DNA Damage through Complex Formation and Acetylation
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...
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Published in | The Journal of biological chemistry Vol. 288; no. 2; pp. 1353 - 1364 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
11.01.2013
American Society for Biochemistry and Molecular Biology |
Subjects | |
Online Access | Get full text |
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Summary: | 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 p21WAF1, 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.
Background: Tumor suppressor p53 plays a pivotal role in the regulation of DNA damage response.
Results: RUNX1 enhances p53 activity in response to DNA damage through elevation of p53 acetylation.
Conclusion: RUNX1 acts as a co-activator for p53 during DNA damage response.
Significance: This study provides novel insight into understanding the molecular mechanisms behind DNA damage-mediated activation of p53. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M112.402594 |