Notch1 modulates timing of G1-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 G1 stabilizes p27 Kip1 and p21 Cip1 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.
Mesh Terms:
3T3 Cells, Animals, Base Sequence, Cell Cycle Proteins, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, DNA, G1 Phase, Humans, Mice, Mice, Knockout, Mice, Transgenic, Models, Biological, RNA Interference, Receptor, Notch1, Receptors, Cell Surface, S Phase, S-Phase Kinase-Associated Proteins, Transcription Factors, Transcription, Genetic, Tumor Suppressor Proteins, Ubiquitin
J. Exp. Med.
Date: Jul. 04, 2005
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