Published 5 July 2005. doi:10.1084/jem.20050559
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 1, 157-168
Notch1 modulates timing of G1-S progression by inducing SKP2 transcription and p27Kip1 degradation
Leonor M. Sarmento1,4,
Hui Huang1,
Ana Limon1,5,
William Gordon1,
Jacquenilson Fernandes1,
Maria J. Tavares3,
Lucio Miele6,
Angelo A. Cardoso3,
Marie Classon2, and
Nadia Carlesso1
1 Center of Regenerative Medicine and Technology, Massachusetts General Hospital
2 Cancer Center, Massachusetts General Hospital
3 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02129
4 IMM, Institute of Molecular Medicine, University of Lisbon, 1649-028 Lisbon, Portugal
5 Science Research Laboratory Inc., Somerville, MA 02143
6 Department of Pharmacodynamics, University of Illinois, Chicago, IL 60612
CORRESPONDENCE Nadia Carlesso: carlesso.nadia{at}mgh.harvard.edu
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.
Abbreviations used: ATRA, all-trans-retinoic acid; CDK, cyclin-dependent kinase; CKI, cyclin-dependent kinase inhibitor; 
E, intracellular with transmembrane domain of Notch; Dll, Delta-like; EMSA, electrophoretic mobility shift assay; GSI, 
-secretase inhibitor; ICN, intracellular domain of Notch; IP, immunoprecipitation; J1, Jagged1; J2, Jagged2; N1, Notch1; N1AS, N1 antisense; Notchic, Notch intracellular domain; SCF, SKP1/CUL1/F-box; siRNA, small interfering RNA; SKP2, S phase kinase–associated protein 2.
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