Impaired degradation of inhibitory subunit of NF-κB (IκB) and β-catenin as a result of targeted disruption of the β-TrCP1 gene

Keiko Nakayama, Shigetsugu Hatakeyama, Shun Ichiro Maruyama, Akira Kikuchi, Kazunori Onoé, Robert A. Good, Keiichi I. Nakayama

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83 Citations (Scopus)

Abstract

β-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 β-TrCP1 targets inhibitory subunit of NF-κB (IκB) proteins and β-catenin for ubiquitylation, the physiological role of β-TrCP1 in mammals has remained unclear. We have now generated mice deficient in β-TrCP1 and shown that the degradation of IκBα and IκBβ is reproducibly, but not completely, impaired in the cells of these animals. The nuclear translocation and DNA-binding activity of NF-κB as well as the ability of this transcription factor to activate a luciferase reporter gene were also inhibited in β-TrCP1-/- cells compared with those apparent in wild-type cells. The subcellular localization of β-catenin was altered markedly in β-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 β-TrCP1-/- mice pared with the corresponding wild-type cells. These results suggest that β-TrCP1 contributes to, but is not absolutely required for, the degradation of IκB and β-catenin and the consequent regulation of the NF-κB and Wnt signaling pathways, respectively. In addition, they implicate β-TrCP1 in the maintenance of ploidy during cell-cycle progression.

Original languageEnglish
Pages (from-to)8752-8757
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number15
DOIs
Publication statusPublished - 2003 Jul 22

ASJC Scopus subject areas

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