| First Author | Secchiero P | Year | 2008 |
| Journal | Blood | Volume | 111 |
| Issue | 3 | Pages | 1287-94 |
| PubMed ID | 18000166 | Mgi Jnum | J:130770 |
| Mgi Id | MGI:3772308 | Doi | 10.1182/blood-2007-05-092031 |
| Citation | Secchiero P, et al. (2008) Activation of the p53 pathway down-regulates the osteoprotegerin expression and release by vascular endothelial cells. Blood 111(3):1287-94 |
| abstractText | 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. |
