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.
Center of Regenerative Medicine and Technology, Massachusetts General Hospital, Boston, MA, USA.
Leonor M
LM
Sarmento
Hui
H
Huang
Ana
A
Limon
William
W
Gordon
Jacquenilson
J
Fernandes
Maria J
MJ
Tavares
Lucio
L
Miele
Angelo A
AA
Cardoso
Marie
M
Classon
Nadia
N
Carlesso
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA / Q000235:genetics; D016193:G1 Phase / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D034622:RNA Interference; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000378:metabolism*; D016196:S Phase / Q000502:physiology*; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D044786:S-Phase Kinase-Associated Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA