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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1287-1294. Prepublished online as a Blood First Edition Paper on November 13, 2007; DOI 10.1182/blood-2007-05-092031. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-05-092031v1 111/3/1287    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Secchiero, P. Articles by Zauli, G. Search for Related Content PubMed PubMed Citation Articles by Secchiero, P. Articles by Zauli, G. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Activation of the p53 pathway down-regulates the osteoprotegerin expression and release by vascular endothelial cells Paola Secchiero1, Federica Corallini1, Erika Rimondi1, Cristina Chiaruttini1, Maria Grazia di Iasio1, Alessandra Rustighi2,3, Giannino Del Sal2,3, and Giorgio Zauli1 1 Department of Morphology and Embryology, University of Ferrara, Ferrara, Italy; 2 Laboratorio Nazionale Consorzio Interuniversitario per le Biotecnologie (LNCIB), Area Science Park, University of Trieste, Trieste, Italy; and 3 Department of Biochemistry, Biophysics and Chemistry of Macromolecules, University of Trieste, Trieste, Italy It has been shown that the expression of osteoprotegerin (OPG) is up-regulated in tumor-associated endothelial cells as well as in the sera of patients affected by both solid tumors and hematologic malignancies. We now report that sera of p53–/– mice contain higher levels of OPG with respect to p53+/+ mice and that endothelial cells, in which p53 was knocked down by siRNA, release increased levels of OPG with respect to mock-transfected cells. Conversely, activation of the p53 pathway by the MDM2 small molecule antagonist Nutlin-3 significantly attenuated both spontaneous and tumor necrosis factor- (TNF-)–induced OPG mRNA and protein release in endothelial cell cultures. OPG promoter functional assays and chromatin immunoprecipitation experiments revealed inhibitory effects of Nutlin-3 on the TNF--induced NF-B DNA binding activity to the OPG promoter. Because OPG inhibits the pro-tumoricidal activity of TNF-related apoptosis-inducing ligand, our findings suggest that, besides its well-documented functions within the malignant cancer cells, the ability of p53 to down-modulate OPG production by endothelial cells may be an additional important mechanism whereby it exerts non–cell-autonomous tumor suppression function. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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