期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2003
卷号：100
期号：15
页码：8752-8757
DOI：10.1073/pnas.1133216100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：{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 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 pared 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.
