Control of Meiotic and Mitotic Progression by the F Box Protein β-Trcp1 In Vivo

Abstract SCF ubiquitin ligases, composed of three major subunits, S kp1, C ul1, and one of many F b ox p roteins (Fbps), control the proteolysis of important cellular regulators. We have inactivated the gene encoding the Fbp β-Trcp1 in mice. β-Trcp1 −/− males show reduced fertility correlating with an accumulation of methaphase I spermatocytes. β-Trcp1 −/− MEFs display a lengthened mitosis, centrosome overduplication, multipolar metaphase spindles, and misaligned chromosomes. Furthermore, cyclin A, cyclin B, and Emi1, an inhibitor of the anaphase promoting complex, are stabilized in mitotic β-Trcp1 −/− MEFs. Indeed, we demonstrate that Emi1 is a bona fide substrate of β-Trcp1. In contrast, stabilization of β-catenin and IκBα, two previously reported β-Trcp1 substrates, does not occur in the absence of β-Trcp1 and instead requires the additional silencing of β-Trcp2 by siRNA. Thus, β-Trcp1 regulates the timely order of meiotic and mitotic events.