Nucleic Acids Research, 2003, Vol. 31, No. 18 5356-5367
© 2003 Oxford University Press
Identification of Daxx interacting with p73, one of the p53 family, and its regulation of p53 activity by competitive interaction with PML
1 Department of Bioscience and Biotechnology/Institute of Bioscience, Sejong University, 98 Kunja-dong, Kwangjin-gu, Seoul 143-747, Korea, 2 Department of Medical Bioscience, Graduate School, Catholic University, Seoul, Korea and 3 Department of Obstetrics and Gynecology, Catholic University Medical College, 505 Bangpo-dong, Secho-gu, Seoul 137-040, Korea
*To whom correspondence should be addressed. Tel: +83 2 3408 3641; Fax: +83 2 3408 3334; Email: umsj{at}sejong.ac.kr. Correspondence may also be addressed to Jong-Sup Park, Tel: +83 2 590 2596; Fax: +83 2 595 8774; Email: jspark{at}cmc.cuk.ac.kr
Present address:
Eun-Joo Kim, Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD 21231, USA
We performed a yeast two-hybrid screen using p73
, which is a member of the p53 family, as bait. We found that the p53 family members were functionally associated with Daxx, which was described originally as a cytoplasmic mediator of Fas signaling, but has been identified recently as a nuclear protein that co-localizes with the promyelocytic leukemia (PML) protein and regulates transcription. Extensive yeast two-hybrid assays indicated a physical interaction between a region including the oligomerization domain (OD) of p73 (amino acids 345–380) or p53 (amino acids 319–360) and amino acids 161–311 and 667–740 (C-terminal S/P/T-rich domain) of hDaxx, which is the common binding region of Fas, ASK1 and PML. This interaction was further confirmed by in vitro GST pull-down and in vivo immunoprecipitation assays. Both Daxx and p73/p53 co-localized in nuclear dot-like structures, which are probably nuclear PML oncogenic domains (PODs) or the nuclear domain NB10. Transient co-expression of Daxx resulted in strong inhibition of p73- and p53-mediated transcriptional activation of the synthetic p53-responsive and p21WAF1 promoters. Consequently, Gal4-Daxx repressed basal transcription in a dose-dependent manner. Treatment with trichostatin A, which is an inhibitor of histone deacetylase, or PML over-expression relieved Daxx-mediated transcriptional repression of p53. The mechanism underlying PML-mediated derepression appears to be competitive binding between Daxx, p53 and PML. Taken together, these findings delineate a transcriptional regulatory network that is modulated by differential Daxx–p53–PML interactions in the nuclear PODs. Therefore, Daxx is implicated in the regulation of the cell cycle and apoptosis through transcriptional regulation of p53 and possibly its family members.
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