Notch1 modulates timing of G(1)-S progression by inducing SKP2 transcription and p27(Kip1) degradation

Cyclin-dependent kinase inhibitors (CKIs) and Notch receptor activation have been shown to influence adult stem cells and progenitors by altering stem cell self-renewal and proliferation. Yet, no interaction between these molecular pathways has been defined. Here we show that ligand-independent and ligand-dependent activation of Notch1 induces transcription of the S phase kinase–associated protein 2 (SKP2), the F-box subunit of the ubiquitin-ligase complex SCF(SKP2) that targets proteins for degradation. Up-regulation of SKP2 by Notch signaling enhances proteasome-mediated degradation of the CKIs, p27(Kip1) and p21(Cip1), and causes premature entry into S phase. Silencing of SKP2 by RNA interference in G(1) stabilizes p27(Kip1) and p21(Cip1) and abolishes Notch effect on G(1)-S progression. Thus, SKP2 serves to link Notch1 activation with the cell cycle machinery. This novel pathway involving Notch/SKP2/CKIs connects a cell surface receptor with proximate mediators of cell cycle activity, and suggests a mechanism by which a known physiologic mediator of cell fate determination interfaces with cell cycle control.