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

Leonor M. Sarmento, Hui Huang, Ana Limon, William Gordon, Jacquenilson Fernandes, Maria J. Tavares, Lucio Miele, Angelo A. Cardoso, Marie Classon, Nadia Carlesso

Research output: Contribution to journalArticle

141 Citations (Scopus)

Abstract

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 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. JEM

Original languageEnglish (US)
Pages (from-to)157-168
Number of pages12
JournalJournal of Experimental Medicine
Volume202
Issue number1
DOIs
StatePublished - Jul 4 2005
Externally publishedYes

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S-Phase Kinase-Associated Proteins
Cyclin-Dependent Kinases
Cell Cycle
Cyclin-Dependent Kinase 2
Notch Receptors
Ligands
Adult Stem Cells
Cell Surface Receptors
Proteasome Endopeptidase Complex
Ligases
Ubiquitin
RNA Interference
Cell Cycle Checkpoints
S Phase
Proteolysis
Up-Regulation

ASJC Scopus subject areas

  • Immunology

Cite this

Notch1 modulates timing of G1-S progression by inducing SKP2 transcription and p27Kip1 degradation. / Sarmento, Leonor M.; Huang, Hui; Limon, Ana; Gordon, William; Fernandes, Jacquenilson; Tavares, Maria J.; Miele, Lucio; Cardoso, Angelo A.; Classon, Marie; Carlesso, Nadia.

In: Journal of Experimental Medicine, Vol. 202, No. 1, 04.07.2005, p. 157-168.

Research output: Contribution to journalArticle

Sarmento, LM, Huang, H, Limon, A, Gordon, W, Fernandes, J, Tavares, MJ, Miele, L, Cardoso, AA, Classon, M & Carlesso, N 2005, 'Notch1 modulates timing of G1-S progression by inducing SKP2 transcription and p27Kip1 degradation', Journal of Experimental Medicine, vol. 202, no. 1, pp. 157-168. https://doi.org/10.1084/jem.20050559
Sarmento, Leonor M. ; Huang, Hui ; Limon, Ana ; Gordon, William ; Fernandes, Jacquenilson ; Tavares, Maria J. ; Miele, Lucio ; Cardoso, Angelo A. ; Classon, Marie ; Carlesso, Nadia. / Notch1 modulates timing of G1-S progression by inducing SKP2 transcription and p27Kip1 degradation. In: Journal of Experimental Medicine. 2005 ; Vol. 202, No. 1. pp. 157-168.
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