期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 100, 期 15, 页码 8752-8757出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1133216100
关键词
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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-kappaB (IkappaB) 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 IkappaBalpha and IkappaBbeta is reproducibly, but not completely, impaired in the cells of these animals. The nuclear translocation and DNA-binding activity of NF-kappaB as well as the ability of this transcription factor to activate a luciferase reporter gene were also inhibited in beta-TrCP1(-1-) 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(-1-) mice pared with the corresponding wild-type cells. These results suggest that beta-TrCPI contributes to, but is not absolutely required for, the degradation Of IkappaB and beta-catenin and the consequent regulation of the NF-kappaB and Wnt signaling pathways, respectively. In addition, they implicate beta-TrCP1 in the maintenance of ploidy during cell-cycle progression.
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