The BCL-2 Family Reunion

Chipuk, Jerry E.; Moldoveanu, Tudor; Llambi, Fabien; Parsons, Matthew S.; Green, Douglas R.

doi:10.1016/j.molcel.2010.01.025

Cited by 1,327 publications

(1,341 citation statements)

References 89 publications

Supporting

Mentioning

1,305

Contrasting

Unclassified

Order By: Relevance

“…Ultimately, interactions between Bcl-2 family proteins result in Bax/Bak oligomerization, conformational change, and insertion into the outer mitochondrial membrane, which triggers mitochondrial outer membrane permeabilization (MOMP) by a mechanism that is not fully understood (Chipuk et al, 2010). The importance of this Bax/Bak checkpoint is underscored by findings from mice doubly deficient for bax and bak, which display defects in developmental cell death and cellular resistance to most forms of stress-induced apoptosis (Lindsten et al, 2000;Wei et al, 2001).…”

Section: Downstream From Bcl-2 Homology Domain 3-only Proteinsmentioning

confidence: 99%

“…Like Bid, Bim is a member of the more potent class of BH3-only protein owing to its ability to bind all antiapoptotic Bcl-2 family proteins and, probably, directly activate Bax/Bak (Chipuk et al, 2010). Alternative splicing gives rise to three main isoforms termed short (S), long (L), and extra-long (EL), with the short form being most potent (O'Connor et al, 1998).…”

Section: Bimmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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.

show abstract

Section: Downstream From Bcl-2 Homology Domain 3-only Proteinsmentioning

confidence: 99%

Section: Bimmentioning

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

View full text Add to dashboard Cite

show abstract

“…The Bcl-2 family, composed of anti-and pro-apoptotic proteins, are major regulators of apoptosis [1][2][3][4] upstream of mitochondrial permeability and caspase activity. Pro-apoptotic proteins include multi-domain proteins, such as Bax and Bak, and their upstream effectors the Bcl-2 homology 3 (BH3)-only proteins, such as Bid, Bim, Puma, Bad, Noxa and so on.…”

mentioning

confidence: 99%

pRb/E2F-1-mediated caspase-dependent induction of Noxa amplifies the apoptotic effects of the Bcl-2/Bcl-xL inhibitor ABT-737

et al. 2013

View full text Add to dashboard Cite

Although Bcl-2 family members control caspase activity by regulating mitochondrial permeability, caspases can, in turn, amplify the apoptotic process upstream of mitochondria by ill-characterized mechanisms. We herein show that treatment with a potent inhibitor of Bcl-2 and Bcl-xL, ABT-737, triggers caspase-dependent induction of the BH3-only protein, Mcl-1 inhibitor, Noxa. RNA interference experiments reveal that induction of Noxa, and subsequent cell death, rely not only on the transcription factor E2F-1 but also on its regulator pRb. In response to ABT-737, pRb is cleaved by caspases into a p68Rb form that still interacts with E2F-1. Moreover, pRb occupies the noxa promoter together with E2F-1, in a caspase-dependent manner upon ABT-737 treatment. Thus, caspases contribute to trigger the mitochondrial apoptotic pathway by coupling Bcl-2/Bcl-xL inhibition to that of Mcl-1, via the pRb/E2F-1-dependent induction of Noxa.

show abstract

“…This hydrophobic region serves as the binding groove of the BH3 domain of Bcl-2 proteins and is required for protein activity especially for dimerization and oligomerization (Suzuki et al 2000). This hydrophobic groove also serves as the binding site for the C-terminal α9 helix of Bax in the inactive conformation and is referred to as the BH3 and C-terminus binding groove or the BC groove (Chipuk et al 2010) (Fig. 3b,.…”

Section: Structural Basis Of Bcl-2 Family Protein Activationmentioning

confidence: 99%

Mitochondrial outer membrane permeabilization: a focus on the role of mitochondrial membrane structural organization

et al. 2017

View full text Add to dashboard Cite

Apoptosis is important in regulating cell death turnover and is mediated by the intrinsic and death receptor-based extrinsic pathways which converge at the mitochondrial outer membrane (MOM) leading to mitochondrial outer membrane permeabilization (MOMP). MOMP results in the release of apoptotic proteins that further activate the downstream pathway of apoptosis. Thus, tight regulation of MOMP is crucial in controlling apoptosis, and a lack of control may lead to tissue and organ malformation and the development of cancers. Despite a growing number of studies focusing on the structure and activity of the proteins involved in mediating MOMP, such as the Bcl-2 family proteins, the mechanism of MOMP is not well understood. In particular, the crucial role of the various structural properties and changes in lipid components of the MOM in mediating the recruitment and activation of different Bcl-2 proteins remains poorly understood. Furthermore, the factors that control the changes in mitochondrial membrane integrity from the initiation to the final disruption of MOM have yet to be clearly defined. In this review, we provide an overview of studies that focus on the mitochondrial membrane with a biophysical analysis of the interactions of the Bcl-2 proteins with the mitochondrial membrane.

show abstract

The BCL-2 Family Reunion

Cited by 1,327 publications

References 89 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

pRb/E2F-1-mediated caspase-dependent induction of Noxa amplifies the apoptotic effects of the Bcl-2/Bcl-xL inhibitor ABT-737

Mitochondrial outer membrane permeabilization: a focus on the role of mitochondrial membrane structural organization

Contact Info

Product

Resources

About