title: Polyubiquitination of the B-cell translocation gene 1 and 2 proteins is promoted by the SCF ubiquitin ligase complex containing βTrCP.
abstract: B-cell translocation gene 1 and 2 (BTG1 and BTG2) are members of the BTG/Tob antiproliferative protein family, which is able to regulate the cell cycle and cell proliferation. We previously reported that BTG1, BTG2, Tob, and Tob2 are degraded via the ubiquitin-proteasome pathway. In this study, we investigated the mechanism of polyubiquitination of BTG1 and BTG2. Since the Skp1-Cdc53/Cullin 1-F-box protein (SCF) complex functions as one of the major ubiquitin ligases for cell cycle regulation, we first examined interactions between BTG proteins and components of the SCF complex, and found that BTG1 and BTG2 were capable of interacting with the SCF complex containing Cullin-1 (a scaffold protein) and Skp1 (a linker protein). As the SCF complex can ubiquitinate various target proteins by substituting different F-box proteins as subunits that recognize different target proteins, we next examined which F-box proteins could bind the two BTG proteins, and found that Skp2, β-transducin repeat-containing protein 1 (βTrCP1), and βTrCP2 were able to associate with both BTG1 and BTG2. Furthermore, we obtained evidence showing that βTrCP1 enhanced the polyubiquitination of both BTG1 and BTG2 more efficiently than Skp2 did, and that an F-box truncated mutant of βTrCP1 had a dominant negative effect on this polyubiquitination. Thus, we propose that BTG1 and BTG2 are subjected to polyubiquitination, more efficiently when it is mediated by SCFβTrCP than by SCFSkp2.
authors.affiliation: Department of Biochemistry, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan. hits@asahikawa-med.ac.jp
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sasajima
authors.forename: Koji
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Kashiwayanagi
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Yokosawa
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism*; D002453:Cell Cycle; D059447:Cell Cycle Checkpoints; D006367:HeLa Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D021122:Protein Subunits; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D054875:Ubiquitination; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism*
chemical_list: D017874:Immediate-Early Proteins; D009363:Neoplasm Proteins; D021122:Protein Subunits; D025521:Tumor Suppressor Proteins; D044844:beta-Transducin Repeat-Containing Proteins; C070114:BTG2 protein, human; C074086:BTG1 protein, human; D044843:SKP Cullin F-Box Protein Ligases; D046988:Proteasome Endopeptidase Complex