The antiangiogenic agent TNP-470 requires p53 and p21CIP/WAF for endothelial cell growth arrest.
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.
Yeh
J R
JR
Departments of Molecular, Cellular, and Developmental Biology, and Pharmacology, Yale University, New Haven, CT 06520-8103, USA.
Mohan
R
R
Crews
C M
CM
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*
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