title: von Hippel-Lindau protein promotes Skp2 destabilization on DNA damage.
abstract: Germline mutations in the von Hippel-Lindau (VHL) tumor suppressor gene cause VHL disease, a rare and autosomal-dominant genetic syndrome. Because VHL protein (pVHL) is the master regulator of hypoxia-inducible factor alpha (HIFα), the most prominent feature of VHL disease is the deregulation of HIFα proteins. However, the precise mechanism by which the loss of pVHL function contributes to tumorigenesis is not fully understood. Here, we show that pVHL destabilizes the F-box protein Skp2, a chief component of Skp, Cullin, F-box-containing complex that promotes DNA synthesis in the S phase. The β-domain of pVHL interacts with Skp2, stimulating proteasome-dependent Skp2 degradation, but the destabilization of Skp2 does not depend on the E3 ubiquitin ligase activity of pVHL. Notably, the generation of DNA damage induces Skp2 degradation, which is attenuated by the suppression of endogenous pVHL expression. One possible mechanism of pVHL-dependent Skp2 degradation entails the antagonizing of Akt-mediated Skp2 phosphorylation, which maintains Skp2 stability. Reintroduction of VHL into VHL-null renal cell carcinoma (RCC) cells decreased Skp2 levels and restored DNA damage-dependent Skp2 degradation. These results identify the tumor suppressor function of pVHL in delaying the S-phase progression to inhibit cell proliferation on DNA damage. Clinically, this report explains as to why Skp2 accumulates abnormally in RCC tissues.
authors.affiliation: National Research Laboratory for Metabolic Checkpoint, Departments of Biomedical Sciences and Biochemistry and Molecular Biology, Cancer Research Institute, Seoul National University College of Medicine, Republic of Korea.
authors.forename: J-S
authors.initials: JS
authors.lastname: Roe
authors.forename: H-R
authors.initials: HR
authors.lastname: Kim
authors.forename: I-Y
authors.initials: IY
authors.lastname: Hwang
authors.forename: E-J
authors.initials: EJ
authors.lastname: Cho
authors.forename: H-D
authors.initials: HD
authors.lastname: Youn
mesh_terms: D017209:Apoptosis; D002292:Carcinoma, Renal Cell / Q000473:pathology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004249:DNA Damage; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology; D007700:Kinetics; D010766:Phosphorylation; D055550:Protein Stability; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016196:S Phase; D044786:S-Phase Kinase-Associated Proteins / Q000737:chemistry* / Q000378:metabolism*; D054875:Ubiquitination; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*
chemical_list: C436291:CDKN1B protein, human; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; C497446:VHL protein, human