title: The antiangiogenic agent TNP-470 requires p53 and p21CIP/WAF for endothelial cell growth arrest.
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.
authors.affiliation: Departments of Molecular, Cellular, and Developmental Biology, and Pharmacology, Yale University, New Haven, CT 06520-8103, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Yeh
authors.forename: R
authors.initials: R
authors.lastname: Mohan
authors.forename: C M
authors.initials: CM
authors.lastname: Crews
mesh_terms: D000328:Adult; D020533:Angiogenesis Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016510:Corneal Neovascularization; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D003510:Cyclohexanes; D004730:Endothelium, Vascular / Q000166:cytology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D012717:Sesquiterpenes / Q000378:metabolism* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D003510:Cyclohexanes; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012717:Sesquiterpenes; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D018844:Cyclin-Dependent Kinases; D000077609:O-(Chloroacetylcarbamoyl)fumagillol