Submitted May 29, 2007
Accepted November 5, 2007
Activation of the p53 pathway down-regulates the osteoprotegerin (OPG) expression and release by vascular endothelial cells
Paola Secchiero*, Federica Corallini, Erika Rimondi, Cristina Chiaruttini, Maria Grazia di Iasio, Alessandra Rustighi, Giannino Del Sal, and Giorgio Zauli
Department of Morphology and Embryology, University of Ferrara, Ferrara, Italy
LNCIB, Area Science Park, University of Trieste, Trieste, Italy
Department of Biochemistry, Biophysics and Chemistry of Macromolecules, University of Trieste, Trieste, Italy
* Corresponding author; email: secchier{at}mail.umbi.umd.edu.
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 hematological 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. Since OPG inhibits the pro-tumoricidal activity of TNF-related apoptosis inducing ligand (TRAIL), 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.
