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Although runt‐related transcription factor 2 (RUNX2) is known to be an essential key transcription factor for osteoblast differentiation and bone formation, RUNX2 also plays a pivotal role in the regulation of p53‐dependent DNA damage response. In the present study, we report that, in addition to p53, RUNX2 downregulates pro‐apoptotic TAp73 during DNA damage‐dependent cell death. Upon adriamycin (ADR) exposure, human osteosarcoma‐derived U2OS cells underwent cell death in association with an upregulation of TAp73 and various p53/TAp73‐target gene products together with RUNX2. Small interfering RNA‐mediated silencing of  p73  resulted in a marked reduction in ADR‐induced p53/TAp73‐target gene expression, suggesting that TAp73 is responsible for the ADR‐dependent DNA damage response. Immunoprecipitation and transient transfection experiments demonstrated that RUNX2 forms a complex with TAp73 and impairs its transcriptional activity. Notably, knockdown of  RUNX2  stimulated ADR‐induced cell death accompanied by a massive induction of  TAp73  expression, indicating that RUNX2 downregulates  TAp73  expression. Consistent with this notion, the overexpression of RUNX2 suppressed ADR‐dependent cell death, which was associated with a remarkable downregulation of  TAp73  and p53/TAp73‐target gene expression. Collectively, our present findings strongly suggest that RUNX2 attenuates the transcriptional activity and ADR‐mediated induction of TAp73, and may provide novel insights into understanding the molecular basis behind the development and/or maintenance of chemoresistance. Thus, we propose that the silencing of  RUNX2  might be an attractive strategy for improving the chemosensitivity of malignant cancers.    Structured digital abstractp73  and  RUNX2   colocalize  by  fluorescence microscopy  ( View interaction )   RUNX2   physically interacts  with  p73  by  anti bait coip  ( 1 ,  2 )

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Runt‐related transcription factor 2 attenuates the transcriptional activity as well as  DNA  damage‐mediated induction of pro‐apoptotic TAp73 to regulate chemosensitivity