THE PAGANO LABORATORY
P U B L I C A T I O N S

Control of meiotic and mitotic progression by the F-box protein ß-Trcp1 in vivo

 

D. Guardavaccaro, Y. Kudo, J. Boulaire, M. Barchi, L. Busino, M. Donzelli, F. Margottin, P. Jackson, Yamasaki L. and M. Pagano

 

Dev. Cell 4: 799–812, 2003

To investigate the role of the F-box protein ß-Trcp1 in growth and development, we have inactivated the gene encoding this protein in mice. ß-Trcp1-/- animals are viable but males show reduced fertility, decreased spermatozoa and an accumulation of metaphase I spermatocytes. ß-Trcp1-/- mouse embryonic fibroblasts (MEFs) display a delayed progression through mitosis and centrosome overduplication associated with the presence of multipolar metaphase spindles and misaligned chromosomes. Furthermore, cyclin A, cyclin B and Emi1, an inhibitor of the Anaphase Promoting Complex/Cyclosome, are stabilized in mitotic ß-Trcp1-/- MEFs. Indeed, we demonstrate that Emi1 is a bona fide substrate of ß-Trcp1 both in vivo and in vitro. In contrast, stabilization of ß-catenin and IkBa, two previously reported ß-Trcp1 substrates, does not occur in the absence of ß-Trcp1 and instead requires the additional silencing of ß-Trcp2 by siRNA. Taken together, these results expose an unexpected and crucial role for ß-Trcp1 in regulating the timely order of meiotic and mitotic events.