title: Daxx cooperates with the Axin/HIPK2/p53 complex to induce cell death.
abstract: Daxx, a death domain-associated protein, has been implicated in proapoptosis, antiapoptosis, and transcriptional regulation. Many factors known to play critically important roles in controlling apoptosis and gene transcription have been shown to associate with Daxx, including the Ser/Thr protein kinase HIPK2, promyelocytic leukemia protein, histone deacetylases, and the chromatin remodeling protein ATRX. Although it is clear that Daxx may exert multiple functions, the underlying mechanisms remain far from clear. Here, we show that Axin, originally identified for its scaffolding role to control beta-catenin levels in Wnt signaling, strongly associates with Daxx at endogenous levels. The Daxx/Axin complex formation is enhanced by UV irradiation. Axin tethers Daxx to the tumor suppressor p53, and cooperates with Daxx, but not DaxxDeltaAxin, which is unable to interact with Axin, to stimulate HIPK2-mediated Ser(46) phosphorylation and transcriptional activity of p53. Interestingly, Axin and Daxx seem to selectively activate p53 target genes, with strong activation of PUMA, but not p21 or Bax. Daxx-stimulated p53 transcriptional activity was significantly diminished by small interfering RNA against Axin; Daxx fails to inhibit colony formation in Axin(-/-) cells. Moreover, UV-induced cell death was attenuated by the knockdown of Axin and Daxx. All these results show that Daxx cooperates with Axin to stimulate p53, and implicate a direct role for Axin, HIPK2, and p53 in the proapoptotic function of Daxx. We have hence unraveled a novel aspect of p53 activation and shed new light on the ultimate understanding of the Daxx protein, perhaps most pertinently, in relation to stress-induced cell death.
authors.affiliation: Key Laboratory of Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Fujian 361005, China.
authors.forename: Qinxi
authors.initials: Q
authors.lastname: Li
authors.forename: Xuan
authors.initials: X
authors.lastname: Wang
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Wu
authors.forename: Yanning
authors.initials: Y
authors.lastname: Rui
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Jifeng
authors.initials: J
authors.lastname: Wang
authors.forename: Xinghao
authors.initials: X
authors.lastname: Wang
authors.forename: Yih-Cherng
authors.initials: YC
authors.lastname: Liou
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Ye
authors.forename: Sheng-Cai
authors.initials: SC
authors.lastname: Lin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D060466:Axin Protein; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism / Q000528:radiation effects; D056970:Co-Repressor Proteins; D045304:Cytochromes c / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D060466:Axin Protein; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D045304:Cytochromes c; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases