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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.

Authors
  • Nakayama, Keiko
  • Hatakeyama, Shigetsugu
  • Maruyama, Shun-ichiro
  • Kikuchi, Akira
  • Onoé, Kazunori
  • Good, Robert A
  • Nakayama, Keiichi I
Type
Published Article
Journal
Proceedings of the National Academy of Sciences of the United States of America
Publication Date
Jul 22, 2003
Volume
100
Issue
15
Pages
8752–8757
Identifiers
PMID: 12843402
Source
Medline
License
Unknown

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.

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