Control of meiotic and mitotic progression by the F box protein beta-Trcp1 in vivo.
SCF ubiquitin ligases, composed of three major subunits, Skp1, Cul1, and one of many F box proteins (Fbps), control the proteolysis of important cellular regulators. We have inactivated the gene encoding the Fbp beta-Trcp1 in mice. beta-Trcp1(-/-) males show reduced fertility correlating with an accumulation of methaphase I spermatocytes. beta-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 beta-Trcp1(-/-) MEFs. Indeed, we demonstrate that Emi1 is a bona fide substrate of beta-Trcp1. In contrast, stabilization of beta-catenin and IkappaBalpha, two previously reported beta-Trcp1 substrates, does not occur in the absence of beta-Trcp1 and instead requires the additional silencing of beta-Trcp2 by siRNA. Thus, beta-Trcp1 regulates the timely order of meiotic and mitotic events.
Guardavaccaro
Daniele
D
Department of Pathology and New York University Cancer Institute, New York University School of Medicine, New York, NY 10016, USA.
Kudo
Yasusei
Y
Boulaire
Jérôme
J
Barchi
Marco
M
Busino
Luca
L
Donzelli
Maddalena
M
Margottin-Goguet
Florence
F
Jackson
Peter K
PK
Yamasaki
Lili
L
Pagano
Michele
M
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D018385:Centrosome / Q000378:metabolism; D019925:Cyclin A / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D005838:Genotype; D007248:Infertility, Male / Q000235:genetics; D008297:Male; D008540:Meiosis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000502:physiology*; D010088:Oxidoreductases; D010641:Phenotype; D011506:Proteins / Q000378:metabolism; D013090:Spermatocytes / Q000502:physiology; D013379:Substrate Specificity; D044844:beta-Transducin Repeat-Containing Proteins
C471643:Btrc protein, mouse; D018797:Cell Cycle Proteins; D019925:Cyclin A; D019926:Cyclin B; C498961:Fbxo5 protein, mouse; C486774:Fbxw1b protein, mouse; C488911:Hpd protein, mouse; D011506:Proteins; D044844:beta-Transducin Repeat-Containing Proteins; D010088:Oxidoreductases; D019204:GTP-Binding Proteins