Molecular Determinants of the Caspase-promoting Activity of Smac/DIABLO and Its Role in the Death Receptor Pathway

Srinivasula, Srinivasa M.; Datta, Pinaki; Fan, Xuejun; Fernandes-Alnemri, Teresa; Huang, Ziwei; Alnemri, Emad S.

doi:10.1074/jbc.c000533200

Cited by 320 publications

(221 citation statements)

References 33 publications

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“…129 Recently, an IAP-neutralizing and therefore apoptosis-promoting mitochondrial protein, termed Leukemia Smac/Diablo, has been identified that obviously plays a critical role in antagonizing the caspase-inhibitory effect of IAPs. 130,131 The role of Smac in tumor biology is as yet unclear but inactivation of this novel player could also result in a resistant phenotype. Thus, death receptor-targeted therapeutic approaches may encounter similar problems as conventional chemo-or radiotherapy.…”

Section: Death Ligands In Cancer Therapymentioning

confidence: 99%

The kiss of death: promises and failures of death receptors and ligands in cancer therapy

et al. 2001

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Section: Death Ligands In Cancer Therapymentioning

confidence: 99%

The kiss of death: promises and failures of death receptors and ligands in cancer therapy

et al. 2001

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“…Active caspase-9 cleaves and activates the effector caspases-3, -6 and -7, which in turn, by cleaving their substrates, complete the apoptotic cell death. Along with cytochrome C the Smac/DIABLO protein is released into the cytoplasm and binds to IAPs, thereby inhibiting them, and consequently allowing the caspases to complete the apoptotic process (Srinivasula et al, 2000). Bcl-x L is an antiapoptotic protein, which similarly to Bcl-2 prevents the mitochondrial membrane disruption (reviewed by .…”

Section: Badmentioning

confidence: 99%

Multiple and synergistic deregulations of apoptosis-controlling genes in pancreatic carcinoma cells

et al. 2003

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Inability to die by apoptosis is one of the reasons for the deregulated growth of tumour cells and the frequently observed failure of chemotherapy. In this study we thought to identify the common and functionally important characteristics responsible for the apoptosis resistance of pancreatic tumour cells. We analysed cell surface expression level of death receptors CD95 and TRAIL-R1-4 as well as the expression profile of sixteen apoptosis-relevant proteins in five pancreatic carcinoma cell lines Capan1, Colo357, PancTuI, Panc89 and Panc1. These data were evaluated in the context of sensitivity towards anti-CD95 and TRAIL-mediated apoptosis. Here we report that except for resistant Panc1 cells, which only marginally expressed CD95, all other cell lines showed comparable levels of CD95 and TRAIL receptors irrespectively of their apoptotic phenotype. Interestingly, we found that the elevated expression of FLIP, Bcl-x L and IAP in parallel with a downregulation of FADD and Bid was common for the resistant cell lines. Consequently, stable overexpression of XIAP, Bcl-x L or dominant negative FADD in sensitive cells significantly reduced the death receptor mediated apoptosis while the overexpression of Bid rendered the resistant cells sensitive.

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“…[5][6][7] The third BIR domain of XIAP has been the most well-studied BIR in terms of defining the consensus IBM sequence. [8][9][10][11] Examples of proteins that bind to BIRs in an IBM-dependent manner include the caspases, 11,12 the second mitochondrial activator of caspase (SMAC -also known as DIABLO) 13,14 and HtrA2 (also known as Omi), 15 and the Drosophila proteins Hid, Grim and Reaper -reviewed in Bangs et al 16 The most documented function of IAP-binding proteins is to compete with caspases, and thereby abrogate caspase regulation.…”

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confidence: 99%

The mechanism of peptide-binding specificity of IAP BIR domains

et al. 2008

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We describe the peptide-binding specificity of the baculoviral IAP repeat (BIR) domains of the human inhibitor of apoptosis (IAP) proteins, X-linked IAP, cellular IAP1 and neuronal apoptosis inhibitory protein (NAIP). Synthetic peptide libraries were used to profile each domain, and we distinguish two types of binding specificity, which we refer to as type II and type III BIR domains. Both types have a dominant selectivity for Ala in the first position of the four N-terminal residues of the peptide ligands, which constitute a core recognition motif. Our analysis allows us to define the signature of type III BIRs that demonstrate a preference for Pro in the third residue of the ligand, resembling the classic IAP-binding motif (IBM). The signature of the type II BIRs was similar to type III, but with a striking absence of specificity for Pro in the third position, suggesting that the definition of an IBM must be modified depending on the type of BIR in question. These findings explain how subtle changes in the peptide-binding groove of IAP BIR domains can significantly alter the target protein selectivity. Our analysis allows for prediction of BIR domain protein-binding preferences, provides a context for understanding the mechanism of peptide selection and heightens our knowledge of the specificity of IAP antagonists that are being developed as cancer therapeutics. Cell Death and Differentiation (2008) 15, 920-928; doi:10.1038/cdd.2008 ; published online 1 February 2008Apoptosis is a highly regulated cellular signaling pathway that results in the elimination of unwanted cells from multicellular animals. The apoptotic signaling cascades can be initiated by various extracellular (extrinsic pathway) or intracellular (intrinsic pathway) stimuli and ultimately converge on the activation of a family of proteases known as the caspasesreviewed in Fuentes-Prior and Salvesen. 1 Once active, caspases cleave a limited number of substrates that results in the destruction of the cell and its eventual disposal by phagocytic cells.Members of the inhibitor of apoptosis (IAP) protein family have the unique ability to attenuate apoptosis induced through both intrinsic and extrinsic stimuli. It is well established that the X-linked IAP (XIAP) is capable of blocking apoptosis by direct inhibition of caspase-3, -7, and -9 -reviewed in Salvesen and Duckett 2 and Eckelman et al. 3 The means by which the other members of the IAP family inhibit apoptosis is less understood. Many IAPs have the capacity to bind caspases, yet lack the ability to directly inhibit the proteolytic activity of these enzymes -reviewed in Eckelman et al. 3 The defining feature of the IAP family is the presence of 1-3 baculoviral IAP repeat (BIR) domains. BIRs are small, B70-residue zinc-coordinated domains that have been identified as the regions essential to the IAP-caspase interaction. The BIR domain(s) are necessary for the antiapoptotic activity of most IAPs. Often a surface groove on the BIR domain endows it with an affinity toward extreme N-terminal epitopes...

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Molecular Determinants of the Caspase-promoting Activity of Smac/DIABLO and Its Role in the Death Receptor Pathway

Cited by 320 publications

References 33 publications

The kiss of death: promises and failures of death receptors and ligands in cancer therapy

The kiss of death: promises and failures of death receptors and ligands in cancer therapy

Multiple and synergistic deregulations of apoptosis-controlling genes in pancreatic carcinoma cells

The mechanism of peptide-binding specificity of IAP BIR domains

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