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PMID:12843402

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Citation

Nakayama, K, Hatakeyama, S, Maruyama, S, Kikuchi, A, Onoé, K, Good, RA and Nakayama, KI (2003) 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. Proc. Natl. Acad. Sci. U.S.A. 100:8752-7

Abstract

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.

Links

PubMed PMC166385 Online version:10.1073/pnas.1133216100

Keywords

Animals; Apoptosis; Cell Division; Cell Nucleus/metabolism; Cells, Cultured; Cytoskeletal Proteins/metabolism; GTP-Binding Proteins/deficiency; GTP-Binding Proteins/genetics; GTP-Binding Proteins/metabolism; Gene Targeting; I-kappa B Proteins/metabolism; Mice; Mice, Knockout; NF-kappa B/antagonists & inhibitors; NF-kappa B/chemistry; NF-kappa B/metabolism; Polyploidy; Protein Subunits; Trans-Activators/metabolism; beta Catenin; beta-Transducin Repeat-Containing Proteins

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:FBW1A

acts_upstream_of_or_within

GO:0030163: protein catabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2669949

P

Seeded From UniProt

complete

MOUSE:FBW1A

acts_upstream_of_or_within

GO:0043122: regulation of I-kappaB kinase/NF-kappaB signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2669949

P

Seeded From UniProt

complete


See also

References

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