CONTROL OF ANGIOGENESIS IN FIBROBLASTS BY P53 REGULATION OF THROMBOSPONDIN-1

As normal cells progress toward malignancy, they must switch to an ang iogenic phenotype to attract the nourishing vasculature that they depe nd on for their growth. In cultured fibroblasts from Li-Fraumeni patie nts, this switch was found to coincide with loss of the wild-type alle le of the p53 tumor suppressor gene and to be the result of reduced ex pression of thrombospondin-1 (TSP-1), a potent inhibitor of angiogenes is. Transfection assays revealed that p53 can stimulate the endogenous TSP-1 gene and positively regulate TSP-1 promoter sequences. These da ta indicate that, in fibroblasts, wild-type p53 inhibits angiogenesis through regulation of TSP-1 synthesis.