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Nuclear Factor (NF)-B–regulated X-chromosome–linked iap Gene Expression Protects Endothelial Cells from Tumor Necrosis Factor –induced Apoptosis

From the Department of Vascular Biology and Thrombosis Research, Vienna International Research and Cooperation Center/University of Vienna, A-1235 Vienna, Austria

By differential screening of tumor necrosis factor (TNF-) and lipopolysaccharide (LPS)- activated endothelial cells (ECs), we have identified a cDNA clone that turned out to be a member of the inhibitor of apoptosis (iap) gene family. iap genes function to protect cells from undergoing apoptotic death in response to a variety of stimuli. These iap genes, hiap1, hiap2, and xiap were found to be strongly upregulated upon treatment of ECs with the inflammatory cytokines TNF-, interleukin 1β, and LPS, reagents that lead to activation of the nuclear transcription factor B (NF-B). Indeed, overexpression of IB, an inhibitor of NF-B, suppresses the induced expression of iap genes and sensitizes ECs to TNF-–induced apoptosis. Ectopic expression of one member of the human iap genes, human X-chromosome–linked iap (xiap), using recombinant adenovirus overrules the IB effect and protects ECs from TNF-– induced apoptosis. We conclude that xiap represents one of the NF-B–regulated genes that counteracts the apoptotic signals caused by TNF- and thereby prevents ECs from undergoing apoptosis during inflammation.

Key Words: activation • inhibitor of apoptosis gene family • endothelial cells • adenovirus • nuclear factor B

Ichiro Kumabashiri's current address is Department of Internal Medicine, Keiju General Hospital, Tomiokamachi 94, Nanao, Japan.

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• Kuenzi, P., Schneider, P., Dobbelaere, D. A. E. (2003). Theileria parva-Transformed T Cells Show Enhanced Resistance to Fas/Fas Ligand-Induced Apoptosis. J. Immunol. 171: 1224-1231 [Abstract] [Full Text]  
• Kashkar, H., Haefs, C., Shin, H., Hamilton-Dutoit, S. J., Salvesen, G. S., Kronke, M., Jurgensmeier, J. M. (2003). XIAP-mediated Caspase Inhibition in Hodgkin's Lymphoma-derived B Cells. JEM 198: 341-347 [Abstract] [Full Text]  
• Bannerman, D. D., Goldblum, S. E. (2003). Mechanisms of bacterial lipopolysaccharide-induced endothelial apoptosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 284: L899-L914 [Abstract] [Full Text]  
• Edelstein, L. C., Lagos, L., Simmons, M., Tirumalai, H., Gelinas, C. (2003). NF-{kappa}B-Dependent Assembly of an Enhanceosome-Like Complex on the Promoter Region of Apoptosis Inhibitor Bfl-1/A1. Mol. Cell. Biol. 23: 2749-2761 [Abstract] [Full Text]  
• Rayet, B., Fan, Y., Gelinas, C. (2003). Mutations in the v-Rel Transactivation Domain Indicate Altered Phosphorylation and Identify a Subset of NF-{kappa}B-Regulated Cell Death Inhibitors Important for v-Rel Transforming Activity. Mol. Cell. Biol. 23: 1520-1533 [Abstract] [Full Text]  
• Bayon, Y., Ortiz, M. A., Lopez-Hernandez, F. J., Gao, F., Karin, M., Pfahl, M., Piedrafita, F. J. (2003). Inhibition of I{kappa}B Kinase by a New Class of Retinoid-Related Anticancer Agents That Induce Apoptosis. Mol. Cell. Biol. 23: 1061-1074 [Abstract] [Full Text]  
• Xiao, C. W., Yan, X., Li, Y., Reddy, S. A. G., Tsang, B. K. (2003). Resistance of Human Ovarian Cancer Cells to Tumor Necrosis Factor {alpha} Is a Consequence of Nuclear Factor {kappa}B-Mediated Induction of Fas-Associated Death Domain-Like Interleukin-1{beta}-Converting Enzyme-Like Inhibitory Protein. Endocrinology 144: 623-630 [Abstract] [Full Text]  
• Lavon, I., Pikarsky, E., Gutkovich, E., Goldberg, I., Bar, J., Oren, M., Ben-Neriah, Y. (2003). Nuclear Factor-{kappa}B Protects the Liver against Genotoxic Stress and Functions Independently of p53. Cancer Res. 63: 25-30 [Abstract] [Full Text]  
• Scaife, C. L., Kuang, J., Wills, J. C., Trowbridge, D. B., Gray, P., Manning, B. M., Eichwald, E. J., Daynes, R. A., Kuwada, S. K. (2002). Nuclear Factor {kappa}B Inhibitors Induce Adhesion-dependent Colon Cancer Apoptosis: Implications for Metastasis. Cancer Res. 62: 6870-6878 [Abstract] [Full Text]  
• Poulaki, V., Mitsiades, C. S., Joussen, A. M., Lappas, A., Kirchhof, B., Mitsiades, N. (2002). Constitutive Nuclear Factor-{kappa}B Activity Is Crucial for Human Retinoblastoma Cell Viability. Am. J. Pathol. 161: 2229-2240 [Abstract] [Full Text]  
• Munzert, G., Kirchner, D., Stobbe, H., Bergmann, L., Schmid, R. M., Dohner, H., Heimpel, H. (2002). Tumor necrosis factor receptor-associated factor 1 gene overexpression in B-cell chronic lymphocytic leukemia: analysis of NF-kappa B/Rel-regulated inhibitors of apoptosis. Blood 100: 3749-3756 [Abstract] [Full Text]  
• Arnt, C. R., Chiorean, M. V., Heldebrant, M. P., Gores, G. J., Kaufmann, S. H. (2002). Synthetic Smac/DIABLO Peptides Enhance the Effects of Chemotherapeutic Agents by Binding XIAP and cIAP1 in Situ. J. Biol. Chem. 277: 44236-44243 [Abstract] [Full Text]  
• Qin, Y., Camoretti-Mercado, B., Blokh, L., Long, C. G., Ko, F. D., Hamann, K. J. (2002). Fas Resistance of Leukemic Eosinophils Is Due to Activation of NF-{kappa}B by Fas Ligation. J. Immunol. 169: 3536-3544 [Abstract] [Full Text]  
• Yin, K.-j., Chen, S.-D., Lee, J.-M., Xu, J., Hsu, C. Y. (2002). ATM Gene Regulates Oxygen-Glucose Deprivation-Induced Nuclear Factor-{kappa}B DNA-Binding Activity and Downstream Apoptotic Cascade in Mouse Cerebrovascular Endothelial Cells. Stroke 33: 2471-2477 [Abstract] [Full Text]  
• You, Z., Madrid, L. V., Saims, D., Sedivy, J., Wang, C.-Y. (2002). c-Myc Sensitizes Cells to Tumor Necrosis Factor-mediated Apoptosis by Inhibiting Nuclear Factor kappa B Transactivation. J. Biol. Chem. 277: 36671-36677 [Abstract] [Full Text]  
• Hull, C., McLean, G., Wong, F., Duriez, P. J., Karsan, A. (2002). Lipopolysaccharide Signals an Endothelial Apoptosis Pathway Through TNF Receptor-Associated Factor 6-Mediated Activation of c-Jun NH2-Terminal Kinase. J. Immunol. 169: 2611-2618 [Abstract] [Full Text]  
• Mori, N., Yamada, Y., Ikeda, S., Yamasaki, Y., Tsukasaki, K., Tanaka, Y., Tomonaga, M., Yamamoto, N., Fujii, M. (2002). Bay 11-7082 inhibits transcription factor NF-kappa B and induces apoptosis of HTLV-I-infected T-cell lines and primary adult T-cell leukemia cells. Blood 100: 1828-1834 [Abstract] [Full Text]  
• Poulaki, V., Mitsiades, C. S., Kotoula, V., Tseleni-Balafouta, S., Ashkenazi, A., Koutras, D. A., Mitsiades, N. (2002). Regulation of Apo2L/Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis in Thyroid Carcinoma Cells. Am. J. Pathol. 161: 643-654 [Abstract] [Full Text]  
• Wang, Y., Chan, S., Tsang, B. K. (2002). Involvement of Inhibitory Nuclear Factor-{kappa}B (NF{kappa}B)-Independent NF{kappa}B Activation in the Gonadotropic Regulation of X-Linked Inhibitor of Apoptosis Expression during Ovarian Follicular Development in Vitro. Endocrinology 143: 2732-2740 [Abstract] [Full Text]  
• Ferreira, C. G., Epping, M., Kruyt, F. A. E., Giaccone, G. (2002). Apoptosis: Target of Cancer Therapy. Clin. Cancer Res. 8: 2024-2034 [Abstract] [Full Text]  
• Werner, A. B., de Vries, E., Tait, S. W. G., Bontjer, I., Borst, J. (2002). Bcl-2 Family Member Bfl-1/A1 Sequesters Truncated Bid to Inhibit Its Collaboration with Pro-apoptotic Bak or Bax. J. Biol. Chem. 277: 22781-22788 [Abstract] [Full Text]  
• Sugita, S., Kohno, T., Yamamoto, K., Imaizumi, Y., Nakajima, H., Ishimaru, T., Matsuyama, T. (2002). Induction of Macrophage-Inflammatory Protein-3{alpha} Gene Expression by TNF-Dependent NF-{kappa}B Activation. J. Immunol. 168: 5621-5628 [Abstract] [Full Text]  

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