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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1287-1294. Prepublished online as a Blood First Edition Paper on November 13, 2007; DOI 10.1182/blood-2007-05-092031. This Article Full Text (PDF) All Versions of this Article: blood-2007-05-092031v1 111/3/1287    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Secchiero, P. Articles by Zauli, G. Search for Related Content PubMed PubMed Citation Articles by Secchiero, P. Articles by Zauli, G. Social Bookmarking                   What's this?  Previous Article  |  Next Article  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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Patino-Garcia, M. Zalacain, C. Folio, C. Zandueta, L. Sierrasesumaga, M. San Julian, G. Toledo, J. De Las Rivas, and F. Lecanda Profiling of Chemonaive Osteosarcoma and Paired-Normal Cells Identifies EBF2 as a Mediator of Osteoprotegerin Inhibition to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis Clin. Cancer Res., August 15, 2009; 15(16): 5082 - 5091. [Abstract] [Full Text] [PDF] O. F. Hatipoglu, S. Hirohata, M. Z. Cilek, H. Ogawa, T. Miyoshi, M. Obika, K. Demircan, R. Shinohata, S. Kusachi, and Y. Ninomiya ADAMTS1 Is a Unique Hypoxic Early Response Gene Expressed by Endothelial Cells J. Biol. Chem., June 12, 2009; 284(24): 16325 - 16333. [Abstract] [Full Text] [PDF] F. Corallini, F. Bossi, A. Gonelli, C. Tripodo, G. Castellino, T. E. Mollnes, F. Tedesco, L. Rizzi, F. Trotta, G. Zauli, et al. The soluble terminal complement complex (SC5b-9) up-regulates osteoprotegerin expression and release by endothelial cells: implications in rheumatoid arthritis Rheumatology, March 1, 2009; 48(3): 293 - 298. [Abstract] [Full Text] [PDF]

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