title: Loss of p53 compensates for alpha v-integrin function in retinal neovascularization.
abstract: alpha(v)-Integrin antagonists block neovascularization in various species, whereas 20% of alpha(v)-integrin null mice are born with many normal looking blood vessels. Given that blockade of alpha(v)-integrins during angiogenesis induces p53 activity, we utilized p53 null mice to elucidate whether loss of p53 can compensate for alpha(v)-integrin function in neovascularization of the retina. Murine retinal vascularization was inhibited by systemic administration of an alpha(v)-integrin antagonist. In contrast, mice lacking p53 were refractory to this treatment, indicating that neovascularization in normal mice depends on alpha(v)-integrin-mediated suppression of p53. Blockade of alpha(v)-integrins during neovascularization resulted in an induction of p21(CIP1) in wild type and, surprisingly, in p53 null retinas, indicating that alpha(v)-integrin ligation regulates p21(CIP1) levels in a p53-independent manner. In conclusion, we demonstrate for the first time an in vivo intracellular mechanism for compensation of integrin function and that p53 and alpha(v)-integrins act in concert during retinal neovascularization.
authors.affiliation: Department of Microbiology, Pathology, and Immunology, Karolinska Institutet, 141 86 Huddinge, Sweden. Staffan.Stromblad@impi.ki.se
authors.forename: Staffan
authors.initials: S
authors.lastname: Strömblad
authors.forename: Arun
authors.initials: A
authors.lastname: Fotedar
authors.forename: Howard
authors.initials: H
authors.lastname: Brickner
authors.forename: Chandra
authors.initials: C
authors.lastname: Theesfeld
authors.forename: Edith
authors.initials: E
authors.lastname: Aguilar de Diaz
authors.forename: Martin
authors.initials: M
authors.lastname: Friedlander
authors.forename: David A
authors.initials: DA
authors.lastname: Cheresh
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology*; D015153:Blotting, Western; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D006579:Heterozygote; D039564:Integrin alphaV; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D018919:Neovascularization, Physiologic; D011485:Protein Binding; D012160:Retina / Q000502:physiology*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000502:physiology*
chemical_list: D015703:Antigens, CD; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D039564:Integrin alphaV; D016159:Tumor Suppressor Protein p53