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Molecular and Cellular Biology, October 2004, p. 8813-8822, Vol. 24, No. 20
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.20.8813-8822.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Notch Activation Induces Endothelial Cell Cycle Arrest and Participates in Contact Inhibition: Role of p21Cip1 Repression{dagger}

Michela Noseda,1,2 Linda Chang,1,3 Graeme McLean,1,3 Jonathan E. Grim,4 Bruce E. Clurman,4 Laura L. Smith,4 and Aly Karsan1,2,3,5*

Department of Medical Biophysics,1 Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency,5 Experimental Medicine Program,3 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada,2 Basic Sciences, Human Biology and Clinical Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington4

Received 11 January 2004/ Returned for modification 4 March 2004/ Accepted 19 July 2004

Although previous studies demonstrate that appropriate Notch signaling is required during angiogenesis and in vascular homeostasis, the mechanisms by which Notch regulates vascular function remain to be elucidated. Here, we show that activation of the Notch pathway by the ligand Jagged1 reduces the proliferation of endothelial cells. Notch activation inhibits proliferation of endothelial cells in a cell-autonomous manner by inhibiting phosphorylation of the retinoblastoma protein (Rb). During cell cycle entry, p21Cip1 is upregulated in endothelial cells. Activated Notch inhibits mitogen-induced upregulation of p21Cip1 and delays cyclin D-cdk4-mediated Rb phosphorylation. Notch-dependent repression of p21Cip1 prevents nuclear localization of cyclin D and cdk4. The necessity of p21Cip1 for nuclear translocation of cyclin D-cdk4 and S-phase entry in endothelial cells was demonstrated by targeted downregulation of p21Cip1 by using RNA interference. We further demonstrate that when endothelial cells reach confluence, Notch is activated and p21Cip1 is downregulated. Inhibition of the Notch pathway at confluence prevents p21Cip1 downregulation and induces Rb phosphorylation. We suggest that Notch activation contributes to contact inhibition of endothelial cells, in part through repression of p21Cip1 expression.

* Corresponding author. Mailing address: British Columbia Cancer Research Centre, 601 West 10th Ave., Vancouver, British Columbia, Canada V5Z 1L3. Phone: (604) 877-6248. Fax: (604) 877-6002. E-mail: akarsan{at}bccrc.ca.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, October 2004, p. 8813-8822, Vol. 24, No. 20
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.20.8813-8822.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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