Transcriptional Factors p53

In contrast to the preceding angiogenic inhibitors, which are secreted or proteolytically activated extracellularly, p53 is a nuclear transcriptional protein. Nevertheless, p53 might induce secreted antiangiogenic protein, including thrombospondin I (51,89), and p53 might inhibit angiogenesis by several additional mechanisms: (1) decrease endothelial cell growth by affecting p21 and the cell cycle or by downregulation of VEGF (90) or bFGF (91,92); (2) promote endothelial cell apoptosis (93,94); (3) inhibit endothelial cell differentiation (95); (4) inhibit breakdown of the extracellular matrix (96).

Therapy with p53 is one of the few molecular approaches that has shown efficacy in humans (97) and it is likely that this antitumor activity is mediated in part by its antiangiogenic mechanism. In one clinical study in which the transfection efficiency with p53-con-taining retrovirus was at most 20%, some of the injected tumors regressed completely. As a result, the authors concluded that apoptosis or cell cycle inhibition of the transfected tumor cell could not account for the amount of tumor inhibition observed and that a bystander effect was responsible. It appears that the bystander antitumor effect of p53 in this and many other studies was partially the result of its antiangiogenic mechanism (51,90,94, 95). With both viral (90,95) and nonviral carriers (51,94,98-100), p53 has demonstrated an antiangiogenic and antitumor effect on an array of different tumors.

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