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Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12782-7.

The antiangiogenic agent TNP-470 requires p53 and p21CIP/WAF for endothelial cell growth arrest.

Author information

1
Departments of Molecular, Cellular, and Developmental Biology, and Pharmacology, Yale University, New Haven, CT 06520-8103, USA.

Abstract

Targeting the endothelial cell cycle as an antiangiogenic strategy has been difficult given the ubiquitous expression of critical cell cycle regulators. Here, we show that the antiangiogenic drug TNP-470 displays striking cell-type specificity insofar as it induces the expression of p21(CIP/WAF), a cyclin-dependent kinase inhibitor, in endothelial cells but not in embryonic or adult fibroblasts. Moreover, primary endothelial cells isolated from p53(-/-) and p21(CIP/WAF-/-) mice are resistant to the cytostatic activity of TNP-470. We also demonstrate that p21(CIP/WAF-/-) mice are resistant to the antiangiogenic activity of TNP-470 in the basic fibroblast growth factor corneal micropocket angiogenesis assay. We conclude that TNP-470 induces p53 activation through a unique mechanism in endothelial cells leading to p21(CIP/WAF) expression and subsequent growth arrest.

PMID:
11070090
PMCID:
PMC18841
DOI:
10.1073/pnas.97.23.12782
[Indexed for MEDLINE]
Free PMC Article

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