Embelin, an Inhibitor of X Chromosome-Linked Inhibitor-of-Apoptosis Protein, Blocks Nuclear Factor-κB (NF-κB) Signaling Pathway Leading to Suppression of NF-κB-Regulated Antiapoptotic and Metastatic Gene Products

2006 ◽  
Vol 71 (1) ◽  
pp. 209-219 ◽  
Author(s):  
Kwang Seok Ahn ◽  
Gautam Sethi ◽  
Bharat B. Aggarwal
Keyword(s):  
Signaling Pathway ◽  
X Chromosome ◽  
Nuclear Factor Κb ◽  
Inhibitor Of Apoptosis ◽  
Nuclear Factor ◽  
Gene Products ◽  
Inhibitor Of Apoptosis Protein ◽  
Apoptosis Protein ◽  
Protein Blocks

scholarly journals Inhibitor of Apoptosis Protein cIAP2 Is Essential for Lipopolysaccharide-Induced Macrophage Survival

2006 ◽  
Vol 26 (2) ◽  
pp. 699-708 ◽  
Author(s):  
Damiano Conte ◽  
Martin Holcik ◽  
Charles A. Lefebvre ◽  
Eric LaCasse ◽  
David J. Picketts ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Potent Inhibitor ◽  
Nuclear Factor Κb ◽  
Innate Immune ◽  
The Other ◽  
Inhibitor Of Apoptosis ◽  
Nuclear Factor ◽  
Inhibitor Of Apoptosis Protein ◽  
Apoptotic Death ◽  
Apoptosis Protein

ABSTRACT The cellular inhibitor of apoptosis 2 (cIAP2/HIAP1) is a potent inhibitor of apoptotic death. In contrast to the other members of the IAP family, cIAP2 is transcriptionally inducible by nuclear factor-κB in response to multiple triggers. We demonstrate here that cIAP2−/− mice exhibit profound resistance to lipopolysaccharide (LPS)-induced sepsis, specifically because of an attenuated inflammatory response. We show that LPS potently upregulates cIAP2 in macrophages and that cIAP2−/− macrophages are highly susceptible to apoptosis in a LPS-induced proinflammatory environment. Hence, cIAP2 is critical in the maintenance of a normal innate immune inflammatory response.

Biologic sequelae of nuclear factor–κB blockade in multiple myeloma: therapeutic applications

Blood ◽  
2002 ◽  
Vol 99 (11) ◽  
pp. 4079-4086 ◽  
Author(s):  
Nicholas Mitsiades ◽  
Constantine S. Mitsiades ◽  
Vassiliki Poulaki ◽  
Dharminder Chauhan ◽  
Paul G. Richardson ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Nuclear Translocation ◽  
Nuclear Factor Κb ◽  
Inhibitor Of Apoptosis ◽  
Caspase 8 ◽  
Nuclear Factor ◽  
Inhibitor Of Apoptosis Protein ◽  
Tnf Α ◽  
Apoptosis Protein ◽  
Induced Apoptosis

The transcription factor nuclear factor–κB (NF-κB) confers significant survival potential in a variety of tumors. Several established or novel anti–multiple myeloma (anti-MM) agents, such as dexamethasone, thalidomide, and proteasome inhibitors (PS-341), inhibit NF-κB activity as part of their diverse actions. However, studies to date have not delineated the effects of specific inhibition of NF-κB activity in MM. We therefore investigated the effect of SN50, a cell-permeable specific inhibitor of NF-κB nuclear translocation and activity, on MM cells. SN50 induced apoptosis in MM cell lines and patient cells; down-regulated expression of Bcl-2, A1, X-chromosome–linked inhibitor-of-apoptosis protein (XIAP), cellular inhibitor-of-apoptosis protein 1 (cIAP-1), cIAP-2, and survivin; up-regulated Bax; increased mitochondrial cytochromec release into the cytoplasm; and activated caspase-9 and caspase-3, but not caspase-8. We have previously demonstrated that tumor necrosis factor–α (TNF-α) is present locally in the bone marrow microenvironment and induces NF-κB–dependent up-regulation of adhesion molecules on both MM cells and bone marrow stromal cells, with resultant increased adhesion. In this study, TNF-α alone induced NF-κB nuclear translocation, cIAP-1 and cIAP-2 up-regulation, and MM cell proliferation; in contrast, SN50 pretreatment sensitized MM cells to TNF-α–induced apoptosis and cleavage of caspase-8 and caspase-3, similar to our previous finding of SN50-induced sensitization to apoptosis induced by the TNF-α family member TNF-related apoptosis-inducing ligand (TRAIL)/Apo2L. Moreover, SN50 inhibited TNF-α–induced expression of another NF-κB target gene, intercellular adhesion molecule–1. Although the p38 inhibitor PD169316 did not directly kill MM cells, it potentiated the apoptotic effect of SN50, suggesting an interaction between the p38 and NF-κB pathways. Our results therefore demonstrate that NF-κB activity in MM cells promotes tumor-cell survival and protects against apoptotic stimuli. These studies provide the framework for targeting NF-κB activity in novel biologically based therapies for MM.

scholarly journals Nuclear Factor-κB-Mediated X-Linked Inhibitor of Apoptosis Protein Expression Prevents Rat Granulosa Cells from Tumor Necrosis Factor α-Induced Apoptosis

Endocrinology ◽  
2001 ◽  
Vol 142 (2) ◽  
pp. 557-563 ◽  
Author(s):  
Chao Wu Xiao ◽  
Kristian Ash ◽  
Benjamin K. Tsang
Keyword(s):  
Granulosa Cells ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Nuclear Factor Κb ◽  
Inhibitor Of Apoptosis ◽  
Nuclear Factor ◽  
Inhibitor Of Apoptosis Protein ◽  
Apoptosis Protein ◽  
Factor Α ◽  
Necrosis Factor

Abstract Although X-linked inhibitor of apoptosis protein (Xiap) is an important intracellular suppressor of apoptosis in a variety of cell types and is present in ovary, its physiological role in follicular development remains unclear. The purpose of the present studies was to examine the modulatory role of Xiap in the proapoptotic action of tumor necrosis factor-α (TNFα) in rat granulosa cells. Granulosa cells from equine CG-primed immature rats were plated in RPMI 1640 medium containing 10% FCS and subsequently cultured in serum-free RPMI in the absence or presence of TNFα (20 ng/ml), the protein synthesis inhibitor cycloheximide (10 μm), and/or adenoviral Xiap sense or antisense complementary DNA. TNFα alone failed to induce granulosa cell death, but in the presence of cycloheximide, it markedly increased the number of apoptotic granulosa cells (as assessed by in situ terminal deoxynucleotidyl transferase-mediated deox-UTPbiotin end labeling and DNA fragmentation analysis). Western analysis indicated that TNFα alone increased the Xiap protein level, a response significantly reduced by adenoviral Xiap antisense expression. Down-regulation of Xiap expression by antisense complementary DNA induced granulosa cell apoptosis, which was potentiated by the cytokine. Inhibition of nuclear factor-κB activation by N-acetyl-cysteine and SN50 suppressed Xiap protein expression and enhanced apoptosis induced by TNFα. The latter phenomenon was readily attenuated by adenoviral Xiap sense expression. In conclusion, these findings suggest that Xiap is an important intracellular modulator of the TNFα death signaling pathway in granulosa cells. Its expression is regulated by the TNFα via a nuclear factor-κB-mediated mechanism.

scholarly journals Pseudomonas aeruginosaDelays Kupffer Cell Death via Stabilization of the X-Chromosome-Linked Inhibitor of Apoptosis Protein

2007 ◽  
Vol 179 (1) ◽  
pp. 505-513 ◽  
Author(s):  
Alix Ashare ◽  
Martha M. Monick ◽  
Amanda B. Nymon ◽  
John M. Morrison ◽  
Matthew Noble ◽  
...  
Keyword(s):  
Cell Death ◽  
X Chromosome ◽  
Kupffer Cell ◽  
Inhibitor Of Apoptosis ◽  
Inhibitor Of Apoptosis Protein ◽  
Apoptosis Protein
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