Mechanisms of Action of Bcl-2 Family Proteins

Shamas‐Din, Aisha; Kale, Justin; Leber, Brian; Andrews, David W.

doi:10.1101/cshperspect.a008714

Cited by 606 publications

(469 citation statements)

References 128 publications

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“…However, PPARγ pretreatment decreased TUNEL positive cells (Figure 2A). The Bcl-2-associated X protein (Bax) is a very important pro-apoptotic protein, which plays important roles in triggering the mitochondrial death cascade, [22][23][24] and PPARγ pretreatment suppressed the over-expression of Bax in our experiment. PPARγ decreases RV inflammation in RVF rats: Inflammation plays an important role in heart failure.…”

Section: Resultsmentioning

confidence: 70%

PPARγ Alleviates Right Ventricular Failure Secondary to Pulmonary Arterial Hypertension in Rats

Xü

Liu

et al. 2017

Int. Heart J.

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SummaryPulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling leading to right ventricular hypertrophy (RVH) and failure. Peroxisome proliferator-activated receptor γ (PPARγ), a member of nuclear receptors, has been proved to ameliorate PAH. However, its effect on PAH-induced right ventricular failure (RVF) remains unknown. Therefore, we investigated the therapeutic potential of PPARγ in preventing monocrotaline (MCT)-induced RV dysfunction. The PAH model was induced by MCT administration. Male rats were administered with MCT to develop PAH and RVF formed by approximately day 30. Significant increase in RV area, RVAW resulted in an ascending RV index. However, the LV function including EF, FS, and LVID did not change significantly. PPARγ agonist prevented PAH-induced RVF by preserving RV index and preventing RVH. PPARγ's beneficial effects seem to result from various factors, including anti-apoptosis, preservation RV index, reversal of inflammation, improvement of glucolipid metabolism, reduction of ROS. In a word, PPARγ agonist prevents the development of RVF.( Int Heart J 2017; 58: 948-956)

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Section: Resultsmentioning

confidence: 70%

PPARγ Alleviates Right Ventricular Failure Secondary to Pulmonary Arterial Hypertension in Rats

Xü

Liu

et al. 2017

Int. Heart J.

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“…Several models have been proposed to describe their dynamic interactions that consequently modulate apoptotic function. We hypothesize that a balance between MCL-1 and BCL-X L expression, and therefore the status of MCL-1 dependency, can switch the mode by which the BCL-2 family of proteins interact to initiate apoptosis: from mode 2 in MCL-1-dependent cells to mode 1 in those cells dependent upon two or more antiapoptotic BCL-2 family members for survival (2,(5)(6)(7). The combined use of highly selective inhibitors of BCL-2 (ABT-199; ref.…”

Section: Discussionmentioning

confidence: 99%

MCL-1 Is a Key Determinant of Breast Cancer Cell Survival: Validation of MCL-1 Dependency Utilizing a Highly Selective Small Molecule Inhibitor

Xiao

Nimmer

Sheppard

et al. 2015

Molecular Cancer Therapeutics

108

116

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Hyperexpression of antiapoptotic BCL-2 family proteins allows cells to survive despite the receipt of signals that would ordinarily induce their deletion, a facet frequently exploited by tumors. Tumors addicted to the BCL-2 family proteins for survival are now being targeted therapeutically. For example, navitoclax, a BCL-2/ BCL-X L /BCL-W inhibitor, is currently in phase I/II clinical trials in numerous malignancies. However, the related family member, MCL-1, limits the efficacy of navitoclax and other chemotherapeutic agents. In the present study, we identify breast cancer cell lines that depend upon MCL-1 for survival and subsequently determine the mechanism of apoptosis mediated by the MCL-1 selective inhibitor A-1210477. We demonstrate that apoptosis resulting from a loss in MCL-1 function requires expression of the proapoptotic protein BAK. However, expression of BCL-X L can limit apoptosis resulting from loss in MCL-1 function through sequestration of free BIM. Finally, we demonstrate substantial synergy between navitoclax and MCL-1 siRNA, the direct MCL-1 inhibitor A-1210477, or the indirect MCL-1 inhibitor flavopiridol, highlighting the therapeutic potential for inhibiting BCL-X L and MCL-1 in breast cancer.

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“…Moreover, all three modes are consistent with both the recently proposed 'unified' and the 'embedded together' models for apoptosis regulation. The primary difference between these models is that the former explicitly states that MODE 2 is dominant, whereas the latter states that all of the interactions are governed by complex regulatable equilibria allowing any mode to be dominant depending on the physiological situation (both models are discussed in detail in Shamas-Din et al 13 ).…”

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confidence: 99%

The apoptotic pore on mitochondria: are we breaking through or still stuck?

Borner

Andrews

2014

Cell Death Differ

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The past 25 years of research has brought us close to understanding the apoptotic form of programmed cell death, a major regulatory mechanism that shapes us during embryogenesis and keeps us properly functional and healthy on a daily basis. We know that mistakes in regulating this process contribute to various human diseases ranging from cancer, autoimmunity, immunodeficiency to neurodegenerative diseases, and we now have novel drugs targeting apoptosisregulatory molecules in development or at hand. Some of these compounds have entered clinical trials and might be beneficial in curing diseases such as cancer, particularly in combination with other classical therapeutics.Apoptosis proceeds through two major signaling pathways, an extrinsic pathway initiated by TNF-like death ligands and an intrinsic pathway involving mitochondrial outer membrane permeabilization (MOMP) triggered by a variety of apoptotic stimuli, such as chemotherapeutic drugs, irradiation, the deprivation of growth factors/cytokines or cell-matrix interactions and others. The molecular mechanisms involved in extrinsic apoptosis signaling induced by TNFa and its related cousin FasL have been largely defined, and basically involve the clustering of their respective receptors and the recruitment and activation of initiator caspases-8 and 10 via the FADD adapter molecule and the subsequent cleavage and activation of the effector caspases-3 and 7 by the initiator caspases. It is also well known that in some particular cells, the extrinsic pathway can crosstalk with the intrinsic pathway via cleavage of the BH3 protein Bid by caspase-8. What might be a deviation of the theme is the signaling pathway induced by the TNF-like ligand TRAIL. In this case, yet unidentified molecules may modulate the caspase-8/caspase-3 activation axis. Moreover, caspase-8 has recently become implicated in novel death signaling pathways that emerge from within the cell such as after viral infection, glucose deprivation or the induction of autophagy. Finally, we know now that under caspase-inhibiting conditions, TNFa can also activate alternative death signaling such as necroptosis, which involves RIP-like protein kinases that may crosstalk with mitochondria.Intrinsic, mitochondria-mediated apoptosis signaling is tightly regulated by members of the Bcl-2 family. A subgroup of the family, the BH3 proteins both 'sense' the apoptotic stimuli by posttranscriptional mechanisms and function as the mediators of transcriptional responses. The full scope of the posttranscriptional mechanisms has not yet been unveiled, but we know that it often exposes and/or structures a particular domain in these proteins, called the BH3 domain, which then is able to activate MOMP via two basic strategies: (i) to bind to the hydrophobic pocket of Bcl-2-like survival factors, such as Bcl-2, Bcl-x L , Bcl-w, Mcl-1 and A1, inhibiting them and thereby releasing the pre-bound third subclass of the family, the Bax and Bak effectors, or (ii) to directly activate Bax and Bak on the mitochondrial membrane. Th...

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Mechanisms of Action of Bcl-2 Family Proteins

Cited by 606 publications

References 128 publications

PPARγ Alleviates Right Ventricular Failure Secondary to Pulmonary Arterial Hypertension in Rats

PPARγ Alleviates Right Ventricular Failure Secondary to Pulmonary Arterial Hypertension in Rats

MCL-1 Is a Key Determinant of Breast Cancer Cell Survival: Validation of MCL-1 Dependency Utilizing a Highly Selective Small Molecule Inhibitor

The apoptotic pore on mitochondria: are we breaking through or still stuck?

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