BH3-only proteins in apoptosis and beyond: an overview

Lomonosova, Elena; Chinnadurai, G.

doi:10.1038/onc.2009.39

Cited by 379 publications

(340 citation statements)

References 223 publications

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“…The BH3-only proteins, which function to activate Bax/Bak, share only one BH domain in common (Strasser, 2005). Together, the Bcl-2 family of proteins constitute a complex network of molecules that regulate cell death by influencing mitochondrial release of apoptogenic proteins in response to physiologic or pathologic stimuli, with the BH3-only proteins the upstream initiators (Lomonosova and Chinnadurai, 2008).…”

Section: Bcl-2 Family Proteinsmentioning

confidence: 99%

In vivoContributions of BH3-Only Proteins to Neuronal Death Following Seizures, Ischemia, and Traumatic Brain Injury

Engel

Plesnila

Prehn

et al. 2011

J Cereb Blood Flow Metab

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The Bcl-2 homology (BH) domain 3-only proteins are a proapoptotic subgroup of the Bcl-2 gene family, which regulate cell death via effects on mitochondria. The BH3-only proteins react to various cell stressors and promote cell death by binding and inactivating antiapoptotic Bcl-2 family members and direct activation of proapoptotic multi-BH domain proteins such as Bax. Here, we review the in vivo evidence for their involvement in the pathophysiology of status epilepticus and contrast it to ischemia and traumatic brain injury. Seizures in rodents activate three potent proapoptotic BH3-only proteins: Bid, Bim, and Puma. Analysis of damage after seizures in mice singly deficient for each BH3-only protein supports a causal role for Puma and to a lesser extent Bim but, surprisingly, not Bid. In ischemia and trauma, where core aspects of the pathophysiology of cell death overlap, multiple BH3-only proteins are also activated and Bid has been shown to be required for neuronal death. The findings suggest that while each neurologic insult activates multiple BH3-only proteins, there may be specificity in their functional contribution. Future challenges include evaluating the remaining BH3-only proteins, explaining different causal contributions, and, if possible, exploring neurologic outcomes in mouse models deficient for multiple BH3-only proteins.

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Section: Bcl-2 Family Proteinsmentioning

confidence: 99%

In vivoContributions of BH3-Only Proteins to Neuronal Death Following Seizures, Ischemia, and Traumatic Brain Injury

Engel

Plesnila

Prehn

et al. 2011

J Cereb Blood Flow Metab

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show abstract

“…Bcl-xL and MDM2 both recognize helical motifs in their partner proteins (pro-apoptotic Bak1 and p53) and act to prevent apoptosis of damaged cells (Lomonosova and Chinnadurai 2008;Kruse and Gu 2009). They are both therefore potentially valuable targets for inducing death in tumor cells.…”

Section: Shapesmentioning

confidence: 99%

Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

Wilson

Arkin

2010

Current Topics in Microbiology and Immunology

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“…While the anti-apoptotic Bcl-2 proteins negatively regulate the activation and activities of Bax/Bak, the BH3-only proteins are known to either directly or indirectly activate Bax/Bak. In response to different apoptotic stimuli, different subsets of the BH3-only proteins are transcriptionally or post-translationally activated, and in turn trigger Bax/Bak activation (9,10). The activated Bax/Bak are responsible for the formation of putative mitochondrial pores, which allow the release of cytochrome c and other apoptogenic factors (11).…”

mentioning

confidence: 99%

Cleavage by Caspase 8 and Mitochondrial Membrane Association Activate the BH3-only Protein Bid during TRAIL-induced Apoptosis

Huang

Zhang

O’Neill

et al. 2016

Journal of Biological Chemistry

106

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The BH3-only protein Bid is known as a critical mediator of the mitochondrial pathway of apoptosis following death receptor activation. However, since full-length Bid possesses potent apoptotic activity, the role of a caspase-mediated Bid cleavage is not established in vivo. In addition, due to the fact that multiple caspases cleave Bid at the same site in vitro, the identity of the Bid-cleaving caspase during death receptor signaling remains uncertain. Moreover, as Bid maintains its overall structure following its cleavage by caspase 8, it remains unclear how Bid is activated upon cleavage. Here, Bid-deficient (Bid KO) colon cancer cells were generated by gene editing, and were reconstituted with wild-type or mutants of Bid. While the loss of Bid blocked apoptosis following treatment by TNF-related apoptosis inducing ligand (TRAIL), this blockade was relieved by re-introduction of the wild-type Bid. In contrast, the caspase-resistant mutant Bid D60E and a BH3 defective mutant Bid G94E failed to restore TRAIL-induced apoptosis. By generating Bid/Bax/Bakdeficient (TKO) cells, we demonstrated that Bid is primarily cleaved by caspase 8, not by effector caspases, to give rise to truncated Bid (tBid) upon TRAIL treatment. Importantly, despite the presence of an intact BH3 domain, a tBid mutant lacking the mitochondrial targeting helices (␣6 and ␣7) showed diminished apoptotic activity. Together, these results for the first time establish that cleavage by caspase 8 and the subsequent association with the outer mitochondrial membrane are two critical events that activate Bid during death receptor-mediated apoptosis.Apoptosis, an efficient cell death program, is primarily mediated through the intrinsic or the extrinsic pathway in response to different stimuli in various cell types. Both pathways lead to the activation of a common set of effector caspases, caspase 3, 6, or 7 (1). In the intrinsic pathway, stress signals, e.g. UV irradiation, serum starvation, DNA damage, etc., elicit discrete intracellular pathways that converge on the mitochondria, causing the release of cytochrome c and other apoptogenic proteins. Once in the cytoplasm, cytochrome c triggers formation of the apoptosome, consisting of cytochrome c, Apaf-1, and procaspase 9, and leads to the auto-activation of caspase 9 (2). In the extrinsic pathway, the death ligands, Fas/Apo1/CD95 ligand (FasL) 3 or Apo2L/TRAIL, bind to their cell surface death receptors Fas/Apo-1/CD95 receptor or death receptors 4/5 (DR4/5), respectively, and trigger their trimerization (3). The trimerized receptors then recruit pro-caspase 8 through the adaptor molecule FADD, and form a death-induced signaling complex (DISC), in which caspase 8 becomes auto-activated (4). Once activated, either caspase 8 or 9, in turn, cleaves and activates the more abundant downstream effector caspases 3, 6, and 7, initiating the execution stage of apoptosis (5).The mitochondrial event responsible for the release of apoptogenic factors in the intrinsic pathway, which is termed mitochondrial outer me...

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BH3-only proteins in apoptosis and beyond: an overview

Cited by 379 publications

References 223 publications

In vivoContributions of BH3-Only Proteins to Neuronal Death Following Seizures, Ischemia, and Traumatic Brain Injury

In vivoContributions of BH3-Only Proteins to Neuronal Death Following Seizures, Ischemia, and Traumatic Brain Injury

Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

Cleavage by Caspase 8 and Mitochondrial Membrane Association Activate the BH3-only Protein Bid during TRAIL-induced Apoptosis

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