A functional link between Wnt signaling and SKP2-independent p27 turnover in mammary tumors

Loss of the CDK inhibitor p27^KIP1 is widely linked with poor prognosis in human cancer. In Wnt10b-expressing mammary tumors, levels of p27^KIP1 were extremely low; conversely, Wnt10b-null mammary cells expressed high levels of this protein, suggesting Wnt-dependent regulation of p27^KIP1. Interestingly we found that Wnt-induced turnover of p27 ^KIP1 was independent from classical SCF^SKP2-mediated degradation in both mouse and human cells. Instead, turnover required Cullin 4A and Cullin 4B, components of an alternative E3 ubiquitin ligase induced in response to active Wnt signaling. We found that CUL4A was a novel Wnt target gene in both mouse and human cells and that CUL4A physically interacted with p27^KIP1 in Wnt-responding cells. We further demonstrated that both Cul4A and Cul4B were required for Wnt-induced p27^KIP1 degradation and S-phase progression. CUL4A and CUL4B are therefore components of a conserved Wnt-induced proteasome targeting (WIPT) complex that regulates p27 ^KIP1 levels and cell cycle progression in mammalian cells.