title: Degradation of Tob1 mediated by SCFSkp2-dependent ubiquitination.
abstract: Tob1, a member of the Tob/BTG family, is involved in the control of G(1)-S progression by suppressing cyclin D1 expression and acts as a tumor suppressor gene. Tob1 was reported to have a quick turnover through the ubiquitin-proteasome pathway, but proteins involved in this process are still unknown. We showed that Skp2, a substrate-targeting subunit of the SCF (Skp1/Cul1/F-box protein) ubiquitin ligase complex, was involved in ubiquitin-dependent degradation of Tob1. Skp2 interacted with Tob1 and facilitated ubiquitination of Tob1 in intact cells as well as in vitro. Skp2 mutants without the F-box or leucine rich repeat were not able to bind to Tob1 and did not enhance ubiquitination of Tob1. Tob1 was stabilized in both Skp2(-/-) mouse fibroblasts and Skp2 knockdown HeLa cells. Moreover, cyclin D1 expression was suppressed in Skp2 knockdown HeLa cells. These data suggest that Tob1 is a novel target for degradation by the SCF-Skp2 ubiquitin ligase.
authors.affiliation: Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hiramatsu
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kitagawa
authors.forename: Toru
authors.initials: T
authors.lastname: Suzuki
authors.forename: Chiharu
authors.initials: C
authors.lastname: Uchida
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hattori
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Oda
authors.forename: Shigetsugu
authors.initials: S
authors.lastname: Hatakeyama
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Konno
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kitagawa
mesh_terms: D002453:Cell Cycle; D002460:Cell Line; D019938:Cyclin D1 / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007668:Kidney; D034622:RNA Interference; D011994:Recombinant Proteins / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D019089:Stem Cell Factor / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; D044786:S-Phase Kinase-Associated Proteins; D019089:Stem Cell Factor; C098669:TOB1 protein, human; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D019938:Cyclin D1