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.
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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.
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