Bax Inhibitor 1 in apoptosis and disease

Robinson, Keith S.; Clements, Abigail; Williams, Ann C.; Berger, Cédric N.; Frankel, Gm

doi:10.1038/onc.2010.636

Cited by 77 publications

(71 citation statements)

References 55 publications

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“…Similarly, a link was established between IRE1 signaling and autophagy induction through the binding of TRAF2 to IRE1 and the downstream activation of JNK ( 108 ). This pathway is repressed under nutrient starvation conditions by the ER-located protein BI-1/ TMBIM6 ( 102 ), a negative regulator of IRE1 ( 103 ) that plays an essential role in numerous cancers ( 109,110 ). Thus, it is easily conceivable that, as for PERK, IRE1 might represent a signifi cant player in the control of autophagy in response to environmental challenges.…”

Section: Tumor Microenvironment and Er Stressmentioning

confidence: 99%

Endoplasmic Reticulum Stress–Activated Cell Reprogramming in Oncogenesis

2015

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Stress induced by the accumulation of unfolded proteins in the endoplasmic reticulum (ER) is observed in many human diseases, including cancers. Cellular adaptation to ER stress is mediated by the unfolded protein response (UPR), which aims at restoring ER homeostasis. The UPR has emerged as a major pathway in remodeling cancer gene expression, thereby either preventing cell transformation or providing an advantage to transformed cells. UPR sensors are highly regulated by the formation of dynamic protein scaffolds, leading to integrated reprogramming of the cells. Herein, we describe the regulatory mechanisms underlying UPR signaling upon cell intrinsic or extrinsic challenges, and how they engage cell transformation programs and/or provide advantages to cancer cells, leading to enhanced aggressiveness or chemoresistance. We discuss the emerging crosstalk between the UPR and related metabolic processes to ensure maintenance of protein homeostasis and its impact on cell transformation and tumor growth.Signifi cance: ER stress signaling is dysregulated in many forms of cancer and contributes to tumor growth as a survival factor, in addition to modulating other disease-associated processes, including cell migration, cell transformation, and angiogenesis. Evidence for targeting the ER stress signaling pathway as an anticancer strategy is compelling, and novel agents that selectively inhibit the UPR have demonstrated preliminary evidence of preclinical effi cacy with an acceptable safety profi le. Cancer Discov; 5(6);

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Section: Tumor Microenvironment and Er Stressmentioning

confidence: 99%

Endoplasmic Reticulum Stress–Activated Cell Reprogramming in Oncogenesis

2015

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“…Overexpression of BI-1 decreases the ER Ca 2þ concentration while BI-1 knockdown increases ER Ca 2þ concentrations (Chae et al 2004). Oligomerization of BI-1 during ER stress promotes Ca 2þ /H þ antiporter activity, thereby releasing ER-stored Ca 2þ , reducing acidification of the cytosol, and supporting cell survival (Robinson et al 2011).…”

Section: Apoptosismentioning

confidence: 99%

Xenobiotic Perturbation of ER Stress and the Unfolded Protein Response

2013

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The proper folding, assembly, and maintenance of cellular proteins is a highly regulated process and is critical for cellular homeostasis. Multiple cellular compartments have adapted their own systems to ensure proper protein folding, and quality control mechanisms are in place to manage stress due to the accumulation of unfolded proteins. When the accumulation of unfolded proteins exceeds the capacity to restore homeostasis, these systems can result in a cell death response. Unfolded protein accumulation in the endoplasmic reticulum (ER) leads to ER stress with activation of the unfolded protein response (UPR) governed by the activating transcription factor 6 (ATF6), inositol requiring enzyme-1 (IRE1), and PKR-like endoplasmic reticulum kinase (PERK) signaling pathways. Many xenobiotics have been shown to influence ER stress and UPR signaling with either pro-survival or pro-death features. The ultimate outcome is dependent on many factors including the mechanism of action of the xenobiotic, concentration of xenobiotic, duration of exposure (acute vs. chronic), cell type affected, nutrient levels, oxidative stress, state of differentiation, and others. Assessing perturbations in activation or inhibition of ER stress and UPR signaling pathways are likely to be informative parameters to measure when analyzing mechanisms of action of xenobiotic-induced toxicity.

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“…Further studies demonstrated that TMBIM6/BI-1 is a six transmembrane-spanning protein, located at the endoplasmic reticulum (ER) that has a relevant role in preventing apoptosis. 5 Remarkably, bioinformatic analysis defined a putative family of at least six highly conserved orthologs of TMBIM6/BI-1containing the consensus motif UPF0005 with unknown function, a domain encoding for six to seven transmembrane-spanning regions. …”

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confidence: 99%

TMBIM3/GRINA is a novel unfolded protein response (UPR) target gene that controls apoptosis through the modulation of ER calcium homeostasis

et al. 2012

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Transmembrane BAX inhibitor motif-containing (TMBIM)-6, also known as BAX-inhibitor 1 (BI-1), is an anti-apoptotic protein that belongs to a putative family of highly conserved and poorly characterized genes. Here we report the function of TMBIM3/GRINA in the control of cell death by endoplasmic reticulum (ER) stress. Tmbim3 mRNA levels are strongly upregulated in cellular and animal models of ER stress, controlled by the PERK signaling branch of the unfolded protein response. TMBIM3/GRINA synergies with TMBIM6/BI-1 in the modulation of ER calcium homeostasis and apoptosis, associated with physical interactions with inositol trisphosphate receptors. Loss-of-function studies in D. melanogaster demonstrated that TMBIM3/GRINA and TMBIM6/BI-1 have synergistic activities against ER stress in vivo. Similarly, manipulation of TMBIM3/GRINA levels in zebrafish embryos revealed an essential role in the control of apoptosis during neuronal development and in experimental models of ER stress. These findings suggest the existence of a conserved group of functionally related cell death regulators across species beyond the BCL-2 family of proteins operating at the ER membrane. Cell Death and Differentiation (2012) 19, 1013-1026 doi:10.1038/cdd.2011; published online 13 January 2012Apoptosis is a conserved cell death mechanism essential for normal development and tissue homeostasis in multicellular organisms. In mammals, the BCL-2 family of proteins is a group of crucial upstream regulators of the caspase cascade, comprising both pro-and anti-apoptotic components. 1Although apoptosis is observed in most multicellular organisms, the BCL-2 family of proteins as a whole is poorly conserved in invertebrates including worms, flies, and other species.1,2 In fact, only two BCL-2 homologues are present in flies with controversial roles in programmed cell death. 3,4 A pioneering screening to identify human genes that prevents BAX toxicity in a yeast assay identified transmembrane BAX inhibitor motif-containing (TMBIM)-6, also known as BAX inhibitor-1 (BI-1), as a new mammalian gene that negatively regulates apoptosis (reviewed in Robinson KS et al. and Reimers K et al. 5,6 ). Further studies demonstrated that TMBIM6/BI-1 is a six transmembrane-spanning protein, located at the endoplasmic reticulum (ER) that has a relevant role in preventing apoptosis. 5 Remarkably, bioinformatic analysis defined a putative family of at least six highly conserved orthologs of TMBIM6/BI-1containing the consensus motif UPF0005 with unknown function, a domain encoding for six to seven transmembrane-spanning regions. 7TMBIM family of proteins includes the founder member TMBIM6/BI-1, TMBIM1/RECS1 (responsive to centrifugal force and shear stress gene 1 protein), TMBIM2/LFG (life guard), TMBIM3/GRINA (glutamate receptor ionotropic NMDA protein 1), TMBIM4/GAAP (Golgi anti-apoptoticassociated protein), and TMBIM5/GHTIM (growth hormoneinducible transmembrane protein). The TMBIM family of proteins is highly conserved in mammals, zebrafish, and flies, with homol...

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Bax Inhibitor 1 in apoptosis and disease

Cited by 77 publications

References 55 publications

Endoplasmic Reticulum Stress–Activated Cell Reprogramming in Oncogenesis

Endoplasmic Reticulum Stress–Activated Cell Reprogramming in Oncogenesis

Xenobiotic Perturbation of ER Stress and the Unfolded Protein Response

TMBIM3/GRINA is a novel unfolded protein response (UPR) target gene that controls apoptosis through the modulation of ER calcium homeostasis

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