Title

p53-mediated inhibition of angiogenesis through up-regulation of a collagen prolyl hydroxylase

UMMS Affiliation

Howard Hughes Medical Institute, Program in Molecular Medicine; Program in Gene Function and Expression

Date

8-19-2006

Document Type

Article

Subjects

*Angiogenesis Inhibitors; Animals; Apoptosis; Autoantigens; Cell Line, Tumor; Collagen; Collagen Type IV; Collagen Type XVIII; Endostatins; Endothelial Cells; Endothelium, Vascular; Gene Expression Regulation, Enzymologic; Genes, p53; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental; Neovascularization, Pathologic; Neovascularization, Physiologic; Peptide Fragments; Procollagen-Proline Dioxygenase; Transcription, Genetic; Transplantation, Heterologous; Tumor Suppressor Protein p53; Up-Regulation

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

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.

Rights and Permissions

Citation: Science. 2006 Aug 18;313(5789):968-71. Link to article on publisher's site

Related Resources

Link to Article in PubMed

PubMed ID

16917063