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Secchiero, P. et al.

Paola Secchiero, Federica Corallini, Erika Rimondi, Cristina Chiaruttini, Maria Grazia di Iasio, Alessandra Rustighi, Giannino Del Sal, Giorgio Zauli,

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.[1]

References

Activation of the p53 pathway down-regulates the osteoprotegerin expression and release by vascular endothelial cells. Secchiero, P., Corallini, F., Rimondi, E., Chiaruttini, C., di Iasio, M.G., Rustighi, A., Del Sal, G., Zauli, G. Blood (2008) [Pubmed]

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