A Novel Ubiquitin Fusion System Bypasses the Mitochondria and Generates Biologically Active Smac/DIABLO

Hunter, Allison M.; Kottachchi, Dan; Lewis, John L.; Duckett, Colin S.; Korneluk, Robert G.; Liston, Peter

doi:10.1074/jbc.c200695200

Cited by 52 publications

(50 citation statements)

References 48 publications

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“…29,30 Of these approaches, we chose the Ub fusion technique (Figure 4a). 30,31 When expressed in HeLa cells, the Ub molecules of these fusion were treated with or without (-) 100 ng/ml TNF for 4 h. Cell lysate samples were prepared from adherent and floating cells, after which the caspase (DEVDase) activity of each lysate sample was measured as described in the Experimental Procedures proteins were almost completely cleaved by endogenous Ubspecific proteases 24 h after transfection, generating DN forms with or without intact IBMs (Figure 4b). Binding between XIAP and each of the mature proteins produced was confirmed by a GST-pull down assay, the results of which indicate that XIAP binds only to proteins with intact IBMs (Figure 4b).…”

Section: Htra2 Cleaves and Inactivates Xiapmentioning

confidence: 99%

Mitochondrial protease Omi/HtrA2 enhances caspase activation through multiple pathways

et al. 2003

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Omi/HtrA2 is a mitochondrial serine protease that is released into the cytosol during apoptosis and promotes cytochrome c (Cyt c)dependent caspase activation by neutralizing inhibitor of apoptosis proteins (IAPs) via its IAP-binding motif. The protease activity of Omi/HtrA2 also contributes to the progression of both apoptosis and caspase-independent cell death. In this study, we found that wild-type Omi/HtrA2 is more effective at caspase activation than a catalytically inactive mutant of Omi/HtrA2 in response to apoptotic stimuli, such as UV irradiation or tumor necrosis factor. Although similar levels of Omi/HtrA2 expression, XIAP-binding activity, and Omi/HtrA2 mitochondrial release were observed among cells transfected with catalytically inactive and wild-type Omi/ HtrA2 protein, XIAP protein expression after UV irradiation was significantly reduced in cells transfected with wild-type Omi/HtrA2. Recombinant Omi/HtrA2 was observed to catalytically cleave IAPs and to inactivate XIAP in vitro, suggesting that the protease activity of Omi/HtrA2 might be responsible for its IAP-inhibiting activity. Extramitochondrial expression of Omi/HtrA2 indirectly induced permeabilization of the outer mitochondrial membrane and subsequent Cyt c-dependent caspase activation in HeLa cells. These results indicate that protease activity of Omi/HtrA2 promotes caspase activation through multiple pathways.

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Section: Htra2 Cleaves and Inactivates Xiapmentioning

confidence: 99%

Mitochondrial protease Omi/HtrA2 enhances caspase activation through multiple pathways

et al. 2003

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“…Strategies to enhance SMAC expression or the use of SMAC peptides have shown to increase chemosensitivity of several cancers in vitro and in xenograft models. [146][147][148][149] The involvement of the NF-kB pathway in many cancers suggests that inhibition of this pathway might provide new tools to fight cancer. Several in vitro studies have shown that inhibition of the NF-kB pathway could induce apoptosis in myeloma, lymphoma and leukemia patient cells and may be beneficial for the treatment of these malignancies.…”

Section: Iaps As Targets For Cancer Therapymentioning

confidence: 99%

Inhibitor of apoptosis proteins: new therapeutic targets in hematological cancer?

Graaf

Witte²,

Jansen

2004

Leukemia

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Apoptosis is an essential process for the selection and survival of lymphocytes. Resistance to apoptosis can promote malignant transformation of hematopoietic cells. Proteins that regulate apoptosis may therefore be critically involved in the development of hematological cancer. A delicate balance between pro-and antiapoptotic mechanisms determines whether a cell death signal can activate the execution of the apoptotic cell death program. The family of inhibitor of apoptosis (IAP) proteins is a recently identified, novel category of apoptosis-regulatory proteins. IAPs can inhibit the activation of caspases that are the executioners of apoptosis, activated by both the extrinsic and intrinsic pathway. IAPs may thereby set the threshold for apoptosis-activation and play a key role in the regulation of apoptotic cell death. IAPs themselves are also subject to strict regulation through feedback mechanisms. This paper focuses on the role of IAP family proteins in the regulation of apoptosis and discusses implications for their involvement in cancer and possible use for cancer therapy, especially in leukemias and lymphomas.

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“…24 In mice, on the other hand, targeted deletion of either XIAP 25 or Smac 26 fails to produce an obvious alteration in apoptosis. These latter observations have not only raised questions about the importance of IAP proteins and their antagonists as apoptotic regulators in mammalian cells, but also have been difficult to reconcile with reports that XIAP overexpression inhibits 9,27 and Smac transfection enhances 11,[20][21][22][23]28 the proapoptotic effects of a variety of stimuli in mammalian tissue culture cells.…”

mentioning

confidence: 96%

The saintly side of Smac/DIABLO: giving anticancer drug-induced apoptosis a boost

Arnt

Kaufmann

2003

Cell Death Differ

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A Novel Ubiquitin Fusion System Bypasses the Mitochondria and Generates Biologically Active Smac/DIABLO

Cited by 52 publications

References 48 publications

Mitochondrial protease Omi/HtrA2 enhances caspase activation through multiple pathways

Mitochondrial protease Omi/HtrA2 enhances caspase activation through multiple pathways

Inhibitor of apoptosis proteins: new therapeutic targets in hematological cancer?

The saintly side of Smac/DIABLO: giving anticancer drug-induced apoptosis a boost

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