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

Research output: Contribution to journalArticle

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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 - Jul 22 2003

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Catenins
Genes
F-Box Proteins
Wnt Signaling Pathway
Polyploidy
Ploidies
Ubiquitination
Ligases
Ubiquitin
Luciferases
Cell Size
Reporter Genes
Mammals
Cell Cycle
Transcription Factors
Fibroblasts
Maintenance
DNA

All Science Journal Classification (ASJC) codes

  • General

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Impaired degradation of inhibitory subunit of NF-κB (IκB) and β-catenin as a result of targeted disruption of the β-TrCP1 gene. / Nakayama, Keiko; Hatakeyama, Shigetsugu; Maruyama, Shun Ichiro; Kikuchi, Akira; Onoé, Kazunori; Good, Robert A.; Nakayama, Keiichi I.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 15, 22.07.2003, p. 8752-8757.

Research output: Contribution to journalArticle

Nakayama, Keiko ; Hatakeyama, Shigetsugu ; Maruyama, Shun Ichiro ; Kikuchi, Akira ; Onoé, Kazunori ; Good, Robert A. ; Nakayama, Keiichi I. / Impaired degradation of inhibitory subunit of NF-κB (IκB) and β-catenin as a result of targeted disruption of the β-TrCP1 gene. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 15. pp. 8752-8757.
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