βTrCP regulates BMI1 protein turnover via ubiquitination and degradation

The polycomb group protein BMI1 has been linked to proliferation, senescence, cancer progression and stem cell phenotype. At present, very little is known about its regulation. Here, we report that BMI1 contains a functional recognition motif for the F box protein beta TrCP, which regulates ubiquitination and proteasome-mediated degradation of various proteins. We show that overexpression of wild-type beta TrCP but not the Delta F mutant of it promotes BMI1 ubiquitination and degradation, and knockdown of beta TrCP results in increased expression of BMI1. Furthermore, a mutant of BMI1 with an altered beta TrCP recognition motif is much more stable than wild-type BMI1. We also show that wild-type BMI1 but not the mutant BMI1 interacts with beta TrCP. Accordingly, compared to wild-type BMI1, mutant protein exhibited increased pro-oncogenic activity. In summary, our findings suggest that beta TrCP regulates turnover of BMI1 and its function relevant to oncogenesis, cellular senescence and aging.