Impaired degradation of inhibitory subunit of NF-kappa B (I kappa B) and beta-catenin as a result of targeted disruption of the beta-TrCP1 gene.
beta-TrCP1 (also known as Fbw1a or FWD1) is the F-box protein component of an Skp1/Cul1/F-box (SCF)-type ubiquitin ligase complex. Although biochemical studies have suggested that beta-TrCP1 targets inhibitory subunit of NF-kappa B(I kappa B) proteins and beta-catenin for ubiquitylation, the physiological role of beta-TrCP1 in mammals has remained unclear. We have now generated mice deficient in beta-TrCP1 and shown that the degradation of I kappa B alpha and I kappa B beta is reproducibly, but not completely, impaired in the cells of these animals. The nuclear translocation and DNA-binding activity of NF-kappa B as well as the ability of this transcription factor to activate a luciferase reporter gene were also inhibited in beta-TrCP1-/- cells compared with those apparent in wild-type cells. The subcellular localization of beta-catenin was altered markedly in beta-TrCP1-/- cells. Furthermore, the rate of proliferation was reduced and both cell size and the percentage of polyploid cells were increased in embryonic fibroblasts derived from beta-TrCP1-/- mice compared with the corresponding wild-type cells. These results suggest that beta-TrCP1 contributes to, but is not absolutely required for, the degradation of I kappa B and beta-catenin and the consequent regulation of the NF-kappa B and Wnt signaling pathways, respectively. In addition, they implicate beta-TrCP1 in the maintenance of ploidy during cell-cycle progression.
Nakayama
Keiko
K
Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Hatakeyama
Shigetsugu
S
Maruyama
Shun-ichiro
S
Kikuchi
Akira
A
Onoé
Kazunori
K
Good
Robert A
RA
Nakayama
Keiichi I
KI
D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D018390:Gene Targeting; D020672:I-kappa B Proteins / Q000378:metabolism*; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011123:Polyploidy; D021122:Protein Subunits; D015534:Trans-Activators / Q000378:metabolism*; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins
C471643:Btrc protein, mouse; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D021122:Protein Subunits; D015534:Trans-Activators; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins; D000072000:NF-KappaB Inhibitor alpha; D019204:GTP-Binding Proteins