Fbxo30 Regulates Mammopoiesis by Targeting the Bipolar Mitotic Kinesin Eg5

Abstract

Fbxo30 is an orphan member of the F-box protein family with no known substrate or function. Here we report that, while Fbxo30(-/-) mice exhibit normal development, growth, lifespan, and fertility, the females fail to nurture their offspring as a result of defective mammopoiesis. Mass spectrometry analysis of Fbxo30-associated proteins revealed that Fbxo30 specifically interacts with the bipolar spindle kinesin EG5 (encoded by Kif11). As a result, Fbxo30 targets Eg5 for ubiquitinylation and controls its oscillation during the cell cycle. Correlated with EG5 dysregulation, Fbxo30(-/-) mammary epithelial cells exhibit multiple defects in centrosome homeostasis, mitotic spindle formation, and proliferation. Effects on proliferation, centrosome homeostasis, and mammopoiesis in the Fbxo30(-/-) mice were rescued through normalization of Eg5 activity using shRNA and/or an EG5 inhibitor. Our data reveal the Fbxo30-Eg5 interaction as a critical checkpoint in mammopoiesis and a critical role for ubiquitinylation-regulated Eg5 oscillation in the cell cycle.