Loss of p53 compensates for alpha v-integrin function in retinal neovascularization.
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.
Strömblad
Staffan
S
Department of Microbiology, Pathology, and Immunology, Karolinska Institutet, 141 86 Huddinge, Sweden. Staffan.Stromblad@impi.ki.se
Fotedar
Arun
A
Brickner
Howard
H
Theesfeld
Chandra
C
Aguilar de Diaz
Edith
E
Friedlander
Martin
M
Cheresh
David A
DA
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*
D015703:Antigens, CD; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D039564:Integrin alphaV; D016159:Tumor Suppressor Protein p53