FBXW8 regulates G1 and S phases of cell cycle progression by restricting β-TrCP1 function.

Abstract

Sequential alteration in the expression levels of cell cycle regulatory proteins is crucial for faithful cell cycle progression to maintain the cellular homeostasis. F-box protein β-TrCP1 is known to control the expression levels of several important cell cycle regulatory proteins. However, how the function of β-TrCP1 is regulated in spatiotemporal manner during cell cycle progression remains elusive. Here, we show that expression levels of β-TrCP1 oscillate during cell cycle progression with a minimum level at the G1 and S phases of cell cycle. Using biochemical, flow cytometry, and immunofluorescence techniques, we found that oscillation of β-TrCP1 expression is controlled by another F-box protein FBXW8. FBXW8 directs the proteasomal degradation of β-TrCP1 in MAPK pathway-dependent manner. Interestingly, we found that the attenuation of β-TrCP1 by FBXW8 is important for Cdc25A-mediated cell cycle transition from G1 phase to S phase as well as DNA damage-free progression of S phase. Overall, our study reveals the intriguing molecular mechanism and significance of maintenance of β-TrCP1 levels during cell cycle progression by FBXW8-mediated proteasomal degradation.