Notch1 modulates timing of G1-S progression by inducing SKP2 transcription and p27Kip1 degradation

• Published in: The Journal of experimental medicine Vol. 202; no. 1; pp. 157 - 168
• Main Authors: Sarmento, Leonor M., Huang, Hui, Limon, Ana, Gordon, William, Fernandes, Jacquenilson, Tavares, Maria J., Miele, Lucio, Cardoso, Angelo A., Classon, Marie, Carlesso, Nadia
• Format: Journal Article
• Language: English
• Published: The Rockefeller University Press 04-07-2005
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20050559

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 SCFSKP2 that targets proteins for degradation. Up-regulation of SKP2 by Notch signaling enhances proteasome-mediated degradation of the CKIs, p27Kip1 and p21Cip1, and causes premature entry into S phase. Silencing of SKP2 by RNA interference in G1 stabilizes p27Kip1 and p21Cip1 and abolishes Notch effect on G1-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.