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David L. Vaux - One of the best experts on this subject based on the ideXlab platform.
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Recent advances in understanding Inhibitor of Apoptosis proteins.
F1000Research, 2018Co-Authors: Najoua Lalaoui, David L. VauxAbstract:The Inhibitor of Apoptosis proteins (IAPs) are a family of proteins that were chiefly known for their ability to inhibit Apoptosis by blocking caspase activation or activity. Recent research has shown that cellular IAP1 (cIAP1), cIAP2, and X-linked IAP (XIAP) also regulate signaling by receptors of the innate immune system by ubiquitylating their substrates. These IAPs thereby act at the intersection of pathways leading to cell death and inflammation. Mutation of IAP genes can impair tissue homeostasis and is linked to several human diseases. Small-molecule IAP antagonists have been developed to treat certain malignant, infectious, and inflammatory diseases. Here, we will discuss recent advances in our understanding of the functions of cIAP1, cIAP2, and XIAP; the consequences of their mutation or dysregulation; and the therapeutic potential of IAP antagonist drugs.
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eLS - Inhibitor of Apoptosis (IAP) and BIR‐containing Proteins
Encyclopedia of Life Sciences, 2009Co-Authors: David L. VauxAbstract:The Inhibitor of Apoptosis (IAP) family of proteins are characterized by presence of one or more baculoviral IAP Repeat (BIR) domains, so they are also termed BIRCs, for ‘BIR-containing’ proteins. The first IAPs were identified in insect-attacking viruses, which use them to inhibit defensive Apoptosis of the host cell. Subsequently, other BIR-containing proteins have been found in organisms from yeasts to mammals. The human IAP XIAP can block Apoptosis by directly inhibiting caspases, whereas cIAP1 and cIAP2 inhibit Apoptosis by reducing caspase-activating signals from tumour necrosis factor (TNF) receptor superfamily members. As the genes for some IAPs are amplified in cancers, they appear to be able to act as oncogenes. IAP-antagonist compounds modelled on the IAP antagonist Smac/Diablo are being developed for the treatment of cancer, and are currently undergoing clinical trials. Key concepts All IAPs bear at least one BIR domain, but not all BIR-containing proteins are Inhibitors of Apoptosis. XIAP can block Apoptosis by directly inhibiting caspases, but cIAP1 and cIAP2 inhibit Apoptosis by reducing caspase-activating signals from TNF receptor superfamily members, and by promoting activation of canonical NFκB pathways rather than noncanonical NFκB pathways. Genes for some IAPs are amplified in cancers, and IAP-antagonist compounds modelled on the IAP antagonist Smac/Diablo are being developed for the treatment of cancer. Survivin and BRUCE are not Apoptosis Inhibitors, but are needed for cell division. Keywords: XIAP; cIAP1; cIAP2; IAP; Survivin; BIR
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determination of cell survival by ring mediated regulation of Inhibitor of Apoptosis iap protein abundance
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: John Silke, Tobias Kratina, Diep Chu, Paul G Ekert, Catherine L Day, Miha Pakusch, David C S Huang, David L. VauxAbstract:Inhibitor of Apoptosis (IAP) proteins, which bind to caspases via their baculoviral IAP repeat domains, also bear RING domains that enable them to promote ubiquitylation of themselves and other interacting proteins. Here we show that the RING domain of cIAP1 allows it to bind directly to the RING of X-linked IAP, causing its ubiquitylation and degradation by the proteasome, thus revealing a mechanism by which IAPs can regulate their abundance. Expression of a construct containing the RING of cellular IAP1 was able to deplete melanoma cells of endogenous X-linked IAP, promoted Apoptosis, and also markedly reduced their clonogenicity when treated with cisplatin. Cross control of protein levels by RING domains may therefore enable their levels to be manipulated therapeutically.
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Inhibitor of Apoptosis proteins and their relatives iaps and other birps
Genome Biology, 2001Co-Authors: Anne M Verhagen, Elizabeth J Coulson, David L. VauxAbstract:Apoptosis is a physiological cell death process important for development, homeostasis and the immune defence of multicellular animals. The key effectors of Apoptosis are caspases, cysteine proteases that cleave after aspartate residues. The Inhibitor of Apoptosis (IAP) family of proteins prevent cell death by binding to and inhibiting active caspases and are negatively regulated by IAP-binding proteins, such as the mammalian protein DIABLO/Smac. IAPs are characterized by the presence of one to three domains known as baculoviral IAP repeat (BIR) domains and many also have a RING-finger domain at their carboxyl terminus. More recently, a second group of BIR-domain-containing proteins (BIRPs) have been identified that includes the mammalian proteins Bruce and Survivin as well as BIR-containing proteins in yeasts and Caenorhabditis elegans. These Survivin-like BIRPs regulate cytokinesis and mitotic spindle formation. In this review, we describe the IAPs and other BIRPs, their evolutionary relationships and their subcellular and tissue localizations.
Martin Holcik - One of the best experts on this subject based on the ideXlab platform.
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IRES in distress: translational regulation of the Inhibitor of Apoptosis proteins XIAP and HIAP2 during cell stress
Cell Death & Differentiation, 2005Co-Authors: Stephen M. Lewis, Martin HolcikAbstract:IRES in distress: translational regulation of the Inhibitor of Apoptosis proteins XIAP and HIAP2 during cell stress
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Endogenous expression of Inhibitor of Apoptosis proteins in facial motoneurons of neonatal and adult rats following axotomy.
Neuroscience, 2003Co-Authors: Lowell T. Mcphail, Jacqueline L. Vanderluit, Christopher B. Mcbride, L.w. Oschipok, Stephen J. Crocker, Daigen Xu, Peter Liston, Martin Holcik, C S Thompson, George S. RobertsonAbstract:Abstract The Inhibitor of Apoptosis protein family members inhibit cell death resulting from a variety of apoptotic stimuli. However, the endogenous expression of neuronal Inhibitor of Apoptosis proteins following axonal injury has not been thoroughly examined. Neonatal facial motoneurons are highly susceptible to axotomy-induced Apoptosis, whereas adult facial motoneurons survive axotomy. We hypothesized that the endogenous expression of Inhibitor of Apoptosis proteins may be involved in the differential susceptibility of adult and neonatal facial motoneurons to axonal injury. In this study, we examined the expression of two endogenous Inhibitor of Apoptosis proteins, neuronal Apoptosis Inhibitory protein and x-linked Inhibitory Apoptosis protein, in adult and neonatal rat facial motoneurons following axotomy. Analyses using reverse-transcription polymerase chain reaction and in situ hybridization indicated that neuronal Apoptosis Inhibitory protein mRNA was increased in neonatal facial nuclei 24 h post axotomy. In the adult, neuronal Apoptosis Inhibitory protein mRNA expression increased at 1, 3, 7 and 14 days post axotomy, while little change in the expression of X-linked Inhibitory Apoptosis protein mRNA was detected at any age or time point time point analyzed. Interestingly, immunohistochemistry using antibodies for neuronal Apoptosis Inhibitory protein and X-linked Inhibitory Apoptosis protein, revealed the level of these proteins was higher in the neonatal motoneurons when compared with the adult. Furthermore, immunohistochemistry and western blot for neuronal Apoptosis Inhibitory protein revealed, in contrast to the observed increase in neuronal Apoptosis Inhibitory protein mRNA, a decline in the expression of neuronal Apoptosis Inhibitory protein following axotomy in the adult, whereas no change in neuronal Apoptosis Inhibitory protein was detected in neonatal facial motoneurons. X-linked Inhibitory Apoptosis protein, as analyzed by immunohistochemistry and western blot, remained unchanged by axotomy in neonatal motoneurons and adult motoneurons. These results indicate differential expression and/or turnover of Inhibitor of Apoptosis proteins in neonatal versus adult facial motoneurons, and suggest the level of Inhibitor of Apoptosis protein expression alone is not an indicator of cell fate following axotomy.
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Translational Upregulation of the X-Linked Inhibitor of Apoptosis
Annals of the New York Academy of Sciences, 2003Co-Authors: Martin HolcikAbstract:The X-linked Inhibitor of Apoptosis protein (XIAP) is the most potent and best studied intrinsic regulator of programmed cell death. The critical role XIAP plays in the control of Apoptosis is also reflected in the complex ways the activity of XIAP is regulated. In addition to regulating the function of the protein, the synthesis of XIAP is also selectively regulated. XIAP is translated by a cap-independent mechanism of translation initiation that is mediated by a unique internal ribosome entry site (IRES) sequence element located in its 5' untranslated region. This allows XIAP mRNA to be actively translated during conditions of cellular stress when the majority of cellular protein synthesis is inhibited. The IRES regulation of XIAP translation points to an important mechanism in the control and regulation of Apoptosis.
Tingjun Fan - One of the best experts on this subject based on the ideXlab platform.
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Inhibitor of Apoptosis proteins and Apoptosis
Acta biochimica et biophysica Sinica, 2008Co-Authors: Yunbo Wei, Tingjun FanAbstract:Apoptosis is a physiological cell death process that plays a critical role in development, homeostasis, and immune defense of multicellular animals. Inhibitor of Apoptosis proteins (IAPs) constitute a family of proteins that possess between one and three baculovirus IAP repeats. Some of them also have a really interesting new gene finger domain, and can prevent cell death by binding and inhibiting active caspases, but are regulated by IAP antagonists. Some evidence also indicates that IAP can modulate the cell cycle and signal transduction. The three main factors, IAPs, IAP antagonists, and caspases, are involved in regulating the progress of Apoptosis in many species. Many studies and assumptions have been focused on the anfractuous interactions between these three main factors to explore their real functional model in order to develop potential anticancer drugs. In this review, we describe the classification, molecular structures, and properties of IAPs and discuss the mechanisms of Apoptosis. We also discuss the promising significance of clinical applications of IAPs in the diagnosis and treatment of malignancy.
Peter Liston - One of the best experts on this subject based on the ideXlab platform.
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amsacta moorei entomopoxvirus Inhibitor of Apoptosis suppresses cell death by binding grim and hid
Journal of Virology, 2005Co-Authors: Qianjun Li, Natasha Schokman, Jenny Mei Ho, Peter Liston, Richard W. MoyerAbstract:Inhibitor of Apoptosis (iap) genes have been identified in the genomes of two independent families of insect viruses, the Baculoviridae and the Entomopoxvirinae. In this report, we examined the functional attributes of the Amsacta moorei entomopoxvirus-encoded IAP protein (AMV-IAP). The binding specificity of the individual baculoviral IAP repeat (BIR) domains of AMV-IAP was investigated by using a random-peptide, phage display library, and sequences similar to the amino termini of proapoptotic Drosophila proteins in the Reaper/Hid/Grim family were identified. Furthermore, the BIR domains of AMV-IAP protein were demonstrated to bind the mammalian IAP Inhibitor Smac through the AVPI tetrapeptide sequence, suggesting that the peptide binding pocket and groove found in the insect and mammalian IAPs is conserved in this viral protein. Interaction analysis implicated BIR1 as the high-affinity site for Grim, while BIR2 interacted more strongly with Hid. Both Grim and Hid were demonstrated to interact with AMV-IAP in vivo, and Grim- or Hid-induced cell death was suppressed when AMV-IAP was coexpressed.
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Endogenous expression of Inhibitor of Apoptosis proteins in facial motoneurons of neonatal and adult rats following axotomy.
Neuroscience, 2003Co-Authors: Lowell T. Mcphail, Jacqueline L. Vanderluit, Christopher B. Mcbride, L.w. Oschipok, Stephen J. Crocker, Daigen Xu, Peter Liston, Martin Holcik, C S Thompson, George S. RobertsonAbstract:Abstract The Inhibitor of Apoptosis protein family members inhibit cell death resulting from a variety of apoptotic stimuli. However, the endogenous expression of neuronal Inhibitor of Apoptosis proteins following axonal injury has not been thoroughly examined. Neonatal facial motoneurons are highly susceptible to axotomy-induced Apoptosis, whereas adult facial motoneurons survive axotomy. We hypothesized that the endogenous expression of Inhibitor of Apoptosis proteins may be involved in the differential susceptibility of adult and neonatal facial motoneurons to axonal injury. In this study, we examined the expression of two endogenous Inhibitor of Apoptosis proteins, neuronal Apoptosis Inhibitory protein and x-linked Inhibitory Apoptosis protein, in adult and neonatal rat facial motoneurons following axotomy. Analyses using reverse-transcription polymerase chain reaction and in situ hybridization indicated that neuronal Apoptosis Inhibitory protein mRNA was increased in neonatal facial nuclei 24 h post axotomy. In the adult, neuronal Apoptosis Inhibitory protein mRNA expression increased at 1, 3, 7 and 14 days post axotomy, while little change in the expression of X-linked Inhibitory Apoptosis protein mRNA was detected at any age or time point time point analyzed. Interestingly, immunohistochemistry using antibodies for neuronal Apoptosis Inhibitory protein and X-linked Inhibitory Apoptosis protein, revealed the level of these proteins was higher in the neonatal motoneurons when compared with the adult. Furthermore, immunohistochemistry and western blot for neuronal Apoptosis Inhibitory protein revealed, in contrast to the observed increase in neuronal Apoptosis Inhibitory protein mRNA, a decline in the expression of neuronal Apoptosis Inhibitory protein following axotomy in the adult, whereas no change in neuronal Apoptosis Inhibitory protein was detected in neonatal facial motoneurons. X-linked Inhibitory Apoptosis protein, as analyzed by immunohistochemistry and western blot, remained unchanged by axotomy in neonatal motoneurons and adult motoneurons. These results indicate differential expression and/or turnover of Inhibitor of Apoptosis proteins in neonatal versus adult facial motoneurons, and suggest the level of Inhibitor of Apoptosis protein expression alone is not an indicator of cell fate following axotomy.
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Human Ovarian Cancer and Cisplatin Resistance: Possible Role of Inhibitor of Apoptosis Proteins1
Endocrinology, 2001Co-Authors: Qiang Feng, Peter Liston, Jong-min Kim, Danielle Schneiderman, Barbara C. Vanderhyden, Wylam Faught, Michael Fung Kee Fung, Mary SentermanAbstract:The Inhibitor of Apoptosis proteins (IAPs) constitutes a family of highly conserved Apoptosis suppressor proteins that were originally identified in baculoviruses. Although IAP homologs have recently been demonstrated to suppress Apoptosis in mammalian cells, their expression and role in human ovarian epithelial cancer and chemotherapy resistance are unknown. In the present study we used cisplatin-sensitive and -resistant human ovarian surface epithelial (hOSE) cancer cell lines and adenoviral antisense and sense complementary DNA expression to examine the role of IAP in the regulation of Apoptosis in human ovarian cancer cells and chemoresistance. Antisense down-regulation of X-linked Inhibitor of Apoptosis protein (Xiap), but not human Inhibitor of Apoptosis protein-2 (Hiap-2), induced Apoptosis in cisplatin-sensitive and, to a lesser extent, in -resistant cells. Cisplatin consistently decreased Xiap content and induced Apoptosis in the cisplatin-sensitive, but not cisplatin-resistant, cells. Hiap-2 expression was either unaffected or inhibited to a lesser extent. The inhibition of IAP protein expression and induction of Apoptosis by cisplatin was time and concentration dependent. Infection of cisplatin-sensitive cells with adenoviral sense Xiap complementary DNA resulted in overexpression of Xiap and markedly attenuated the ability of cisplatin to induce Apoptosis. Immunohistochemical localization of the IAPs in hOSE tumors demonstrated the presence of Xiap and Hiap-2, with their levels being highest in proliferative, but not apoptotic, epithelial cells. These studies indicate that Xiap is an important element in the control of ovarian tumor growth and may be a point of regulation for cisplatin in the induction of Apoptosis. These results suggest that the ability of cisplatin to down-regulate Xiap content may be an important determinant of chemosensitivity in hOSE cancer.
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The X-linked Inhibitor of Apoptosis (XIAP) prevents cell death in axotomized CNS neurons in vivo.
Cell death and differentiation, 2000Co-Authors: Sebastian Kügler, Peter Liston, Guido Straten, F Kreppel, Stefan Isenmann, Mathias BährAbstract:The X-linked Inhibitor of Apoptosis (XIAP) prevents cell death in axotomized CNS neurons in vivo
David V. Goeddel - One of the best experts on this subject based on the ideXlab platform.
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The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral Inhibitor of Apoptosis proteins
Cell, 1995Co-Authors: Mike Rothe, Ming Gui Pan, T. Merrill Ayres, William J Henzel, David V. GoeddelAbstract:The 75 kDa tumor necrosis factor receptor (TNFR2) transduces extracellular signals via receptor-associated cytoplasmic proteins. Two of these signal transducers, TRAF1 and TRAF2, were isolated and characterized previously. We report here the biochemical purification and subsequent molecular cloning of two novel TNFR2-associated proteins, designated c-IAP1 and c-IAP2, that are closely related mammalian members of the Inhibitor of Apoptosis protein (IAP) family orginally identified in baculoviruses. The viral and cellular IAPs contain N-terminal baculovirus IAP repeat (BIR) motifs and a C-terminal RING finger. The c-IAPs do not directly contact TNFR2, but rather associate with TRAF1 and TRAF2 through their N-terminal BIR motif-comprising domain. The recruitment of c-IAP1 or c-IAP2 to the TNFR2 signaling complex requires a TRAF2-TRAF1 heterocomplex. © 1995.