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Science 313 (5789): 968-971

Copyright © 2006 by the American Association for the Advancement of Science

p53-Mediated Inhibition of Angiogenesis Through Up-Regulation of a Collagen Prolyl Hydroxylase

Jose G. Teodoro, Albert E. Parker, Xiaochun Zhu, Michael R. Green*

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.

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.

* To whom correspondence should be addressed. E-mail: michael.green{at}umassmed.edu


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