title: Axin stimulates p53 functions by activation of HIPK2 kinase through multimeric complex formation.
abstract: Axin and p53 are tumor suppressors, controlling cell growth, apoptosis, and development. We show that Axin interacts with homeodomain-interacting protein kinase-2 (HIPK2), which is linked to UV-induced p53-dependent apoptosis by interacting with, and phosphorylating Ser 46 of, p53. In addition to association with p53 via HIPK2, Axin contains a separate domain that directly interacts with p53 at their physiological concentrations. Axin stimulates p53-dependent reporter transcription in 293 cells, but not in 293T, H1299, or SaOS-2 cells that are defective in p53 signaling. Axin, but not AxindeltaHIPK2, activates HIPK2-mediated p53 phosphorylation at Ser 46, facilitating p53-dependent transcriptional activity and apoptosis. Specific knockdown of Axin by siRNA reduced UV-induced Ser-46 phosphorylation and apoptosis. Kinase-dead HIPK2 reduced Axin-induced p53-dependent transcriptional activity, indicating that Axin stimulates p53 function through HIPK2 kinase activity. Interestingly, HIPK2deltaAxin that lacks its Axin-binding region acts as a dominant-positive form in p53 activation, suggesting that the Axin-binding region of HIPK2 is a putative autoinhibitory domain. These results show that Axin acts as a tumor suppressor by facilitating p53 function through integration of multiple factors.
authors.affiliation: Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Yanning
authors.initials: Y
authors.lastname: Rui
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xu
authors.forename: Shuyong
authors.initials: S
authors.lastname: Lin
authors.forename: Qinxi
authors.initials: Q
authors.lastname: Li
authors.forename: Hongliang
authors.initials: H
authors.lastname: Rui
authors.forename: Wen
authors.initials: W
authors.lastname: Luo
authors.forename: Hai-Meng
authors.initials: HM
authors.lastname: Zhou
authors.forename: Po-Yan
authors.initials: PY
authors.lastname: Cheung
authors.forename: Zhenguo
authors.initials: Z
authors.lastname: Wu
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Ye
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Jiahuai
authors.initials: J
authors.lastname: Han
authors.forename: Sheng-Cai
authors.initials: SC
authors.lastname: Lin
mesh_terms: D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects; D060466:Axin Protein; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D017930:Genes, Reporter; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012694:Serine / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*; D014466:Ultraviolet Rays
chemical_list: D060466:Axin Protein; D002352:Carrier Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D012694:Serine; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases