This study investigates the role of p53 in regulating tumor angiogenesis by targeting hypoxia-inducible factor 1α (HIF-1α) for degradation. The authors demonstrate that homozygous deletion of the p53 tumor suppressor gene in human cancer cells promotes neovascularization and growth of tumor xenografts in nude mice. They find that p53 inhibits HIF-1 activity by promoting the ubiquitination and proteasomal degradation of HIF-1α, a subunit of the HIF-1 heterodimer. Loss of p53 enhances HIF-1α levels and increases HIF-1-dependent transcriptional activation of the vascular endothelial growth factor (VEGF) gene in response to hypoxia. Forced expression of HIF-1α in p53-expressing tumor cells further increases VEGF expression and neovascularization. These findings suggest that the activation of the angiogenic switch during tumorigenesis is driven by the amplification of normal HIF-1-dependent responses to hypoxia through the loss of p53 function. The study provides insights into the molecular mechanisms underlying the angiogenic switch and highlights the potential therapeutic targets for inhibiting tumor angiogenesis.This study investigates the role of p53 in regulating tumor angiogenesis by targeting hypoxia-inducible factor 1α (HIF-1α) for degradation. The authors demonstrate that homozygous deletion of the p53 tumor suppressor gene in human cancer cells promotes neovascularization and growth of tumor xenografts in nude mice. They find that p53 inhibits HIF-1 activity by promoting the ubiquitination and proteasomal degradation of HIF-1α, a subunit of the HIF-1 heterodimer. Loss of p53 enhances HIF-1α levels and increases HIF-1-dependent transcriptional activation of the vascular endothelial growth factor (VEGF) gene in response to hypoxia. Forced expression of HIF-1α in p53-expressing tumor cells further increases VEGF expression and neovascularization. These findings suggest that the activation of the angiogenic switch during tumorigenesis is driven by the amplification of normal HIF-1-dependent responses to hypoxia through the loss of p53 function. The study provides insights into the molecular mechanisms underlying the angiogenic switch and highlights the potential therapeutic targets for inhibiting tumor angiogenesis.