Activation of the p53 pathway down-regulates the osteoprotegerin expression and release by vascular endothelial cells.
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.
Secchiero
Paola
P
Department of Morphology and Embryology, University of Ferrara, Ferrara, Italy. secchier@mail.umbi.umd.edu
Corallini
Federica
F
Rimondi
Erika
E
Chiaruttini
Cristina
C
di Iasio
Maria Grazia
MG
Rustighi
Alessandra
A
Del Sal
Giannino
G
Zauli
Giorgio
G
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*
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