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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
Author(s) -
Ozaki Toshinori,
Sugimoto Hirokazu,
Nakamura Mizuyo,
Hiraoka Kiriko,
Yoda Hiroyuki,
Sang Meixiang,
Fujiwara Kyoko,
Nagase Hiroki
Publication year - 2015
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13108
Subject(s) - gene knockdown , transcription factor , gene silencing , downregulation and upregulation , runx2 , cancer research , microbiology and biotechnology , biology , apoptosis , transfection , transcription (linguistics) , promoter , programmed cell death , dna damage , regulation of gene expression , gene expression , cell culture , gene , dna , genetics , linguistics , philosophy
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 )