p53-mediated inhibition of angiogenesis through up-regulation of a collagen prolyl hydroxylase.
Recent evidence suggests that antiangiogenic therapy is sensitive to p53 status in tumors, implicating a role for p53 in the regulation of angiogenesis. Here we show that p53 transcriptionally activates the alpha(II) collagen prolyl-4-hydroxylase [alpha(II)PH] gene, resulting in the extracellular release of antiangiogenic fragments of collagen type 4 and 18. Conditioned media from cells ectopically expressing either p53 or alpha(II)PH selectively inhibited growth of primary human endothelial cells. When expressed intracellularly or exogenously delivered, alpha(II)PH significantly inhibited tumor growth in mice. Our results reveal a genetic and biochemical linkage between the p53 tumor suppressor pathway and the synthesis of antiangiogenic collagen fragments.
Teodoro
Jose G
JG
Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
Parker
Albert E
AE
Zhu
Xiaochun
X
Green
Michael R
MR
D020533:Angiogenesis Inhibitors; D000818:Animals; D017209:Apoptosis; D001324:Autoantigens / Q000378:metabolism; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism*; D024141:Collagen Type IV / Q000378:metabolism; D043170:Collagen Type XVIII / Q000378:metabolism; D043169:Endostatins / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology; D004730:Endothelium, Vascular / Q000166:cytology; D015971:Gene Expression Regulation, Enzymologic; D016158:Genes, p53; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D010446:Peptide Fragments / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D015854:Up-Regulation
D020533:Angiogenesis Inhibitors; D001324:Autoantigens; D024141:Collagen Type IV; D043170:Collagen Type XVIII; D043169:Endostatins; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53; C057112:type IV collagen alpha3 chain; D003094:Collagen; D011393:Procollagen-Proline Dioxygenase