Activation of the p53 pathway down-regulates the osteoprotegerin expression and release by vascular endothelial cells

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

Research output: Contribution to journalArticle

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-α (TNF-α)-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-α-induced NF-κB DNA binding activity to the OPG promoter. Because OPG inhibits the protumoricidal 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.

Original languageEnglish
Pages (from-to)1287-1294
Number of pages8
JournalBlood
Volume111
Issue number3
DOIs
Publication statusPublished - 2008

ASJC Scopus subject areas

  • Hematology

Fingerprint Dive into the research topics of 'Activation of the p53 pathway down-regulates the osteoprotegerin expression and release by vascular endothelial cells'. Together they form a unique fingerprint.

Cite this