title: Suppression of p53 activity through the cooperative action of Ski and histone deacetylase SIRT1.
abstract: Ski was originally identified as an oncogene based on the fact that Ski overexpression transformed chicken and quail embryo fibroblasts. Consistent with these proposed oncogenic roles, Ski is overexpressed in various human tumors. However, whether and how Ski functions in mammalian tumorigenesis has not been fully investigated. Here, we show that Ski interacts with p53 and attenuates the biological functions of p53. Ski overexpression attenuated p53-dependent transactivation, whereas Ski knockdown enhanced the transcriptional activity of p53. Interestingly, Ski bound to the histone deacetylase SIRT1 and stabilized p53-SIRT1 interaction to promote p53 deacetylation, which subsequently decreased the DNA binding activity of p53. Consistent with the ability of Ski to inactivate p53, overexpressing Ski desensitized cells to genotoxic drugs and Nutlin-3, a small-molecule antagonist of Mdm2 that stabilizes p53 and activates the p53 pathway, whereas knocking down Ski increased the cellular sensitivity to these agents. These results indicate that Ski negatively regulates p53 and suggest that the p53-Ski-SIRT1 axis is an attractive target for cancer therapy.
authors.affiliation: Division of Biochemistry, Cancer Institute of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Inoue
authors.forename: Shun-ichiro
authors.initials: S
authors.lastname: Iemura
authors.forename: Tohru
authors.initials: T
authors.lastname: Natsume
authors.forename: Keiji
authors.initials: K
authors.lastname: Miyazawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Imamura
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D045744:Cell Line, Tumor; D002645:Chickens; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000235:genetics; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D007093:Imidazoles; D010879:Piperazines; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C060614:SKI protein, human; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C447939:SIRT1 protein, human; D056564:Sirtuin 1