title: Activation of the p53 pathway down-regulates the osteoprotegerin expression and release by vascular endothelial cells.
abstract: 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-alpha (TNF-alpha)-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-alpha-induced NF-kappaB 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.
authors.affiliation: Department of Morphology and Embryology, University of Ferrara, Ferrara, Italy. secchier@mail.umbi.umd.edu
authors.forename: Paola
authors.initials: P
authors.lastname: Secchiero
authors.forename: Federica
authors.initials: F
authors.lastname: Corallini
authors.forename: Erika
authors.initials: E
authors.lastname: Rimondi
authors.forename: Cristina
authors.initials: C
authors.lastname: Chiaruttini
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: di Iasio
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rustighi
authors.forename: Giannino
authors.initials: G
authors.lastname: Del Sal
authors.forename: Giorgio
authors.initials: G
authors.lastname: Zauli
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D053244:Osteoprotegerin / Q000378:metabolism*; D010879:Piperazines / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D007093:Imidazoles; D016328:NF-kappa B; D053244:Osteoprotegerin; D010879:Piperazines; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3