Physiological and Pharmacological Control of BAK, BAX, and Beyond

Luna-Vargas, Mark P.A.; Chipuk, Jerry E.

doi:10.1016/j.tcb.2016.07.002

Cited by 133 publications

(86 citation statements)

References 82 publications

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“…On the contrary, Bax is a key protein in the pro-apoptotic family. Bax can promote the permeabilization and release of cytochrome c and ROS, resulting the activation of the apoptosis cascade (22). In the current study, our data indicates that CLP induces a dramatic increase in Bax expression and a decrease in Bcl-2 expression in the kidney, which were alleviated by Pte treatment.…”

Section: Discussionsupporting

confidence: 57%

Pterostilbene attenuates acute kidney injury in septic mice

et al. 2018

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Abstract. Acute kidney injury (AKI) is a severe complication of sepsis with a high mortality and morbidity. Pterostilbene (Pte) has been suggested to confer anti-apoptotic and anti-inflammatory effects. In the current study, the effects of Pte on AKI were evaluated in septic mice. Cecal ligation and puncture surgery was performed to induce sepsis. The results suggested that Pte administration significantly decreased the levels of serum urea nitrogen and creatinine, and improved the survival rate of septic mice. Additionally, the renal injury induced by sepsis was attenuated by pterostilbene treatment. Notably, pterostilbene reduced Bcl-2-associated X protein expression, and levels of interleukin-1β and tumor necrosis factor-α, and upregulated B-cell lymphoma 2 expression. The results indicate that pterostilbene may serve as a potential therapeutic candidate for the treatment of AKI induced by sepsis.

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Section: Discussionsupporting

confidence: 57%

Pterostilbene attenuates acute kidney injury in septic mice

et al. 2018

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“…Since the discovery of pro-apoptotic BAX more than two decades ago (Olitvai et al, 1993), numerous studies have provided evidence that BAX is a critical protein that controls the gateway to mitochondrial outer membrane permeabilization and apoptosis (Luna-Vargas and Chipuk, 2016; Walensky and Gavathiotis, 2011; Wei et al, 2001). Direct BAX activation by select BH3-only proteins such as BIM, BID and PUMA has been established as a physiological mechanism that initiates the mitochondrial apoptotic pathway during development and homeostasis (Ren et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…cytochrome c , and Smac/Diablo that activate the caspase cascade of apoptosis (Luna-Vargas and Chipuk, 2016; Walensky and Gavathiotis, 2011). Cells deficient for BAX become less sensitive to various apoptotic stimuli and become resistant when both BAX and BAK are deleted (Wei et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Direct Activation of BAX by BTSA1 Overcomes Apoptosis Resistance in Acute Myeloid Leukemia

et al. 2017

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SUMMARY The BCL-2 family protein BAX is a central mediator of apoptosis. Overexpression of anti-apoptotic BCL-2 proteins contributes to tumor development and resistance to therapy by suppressing BAX and its activators. We report the discovery of BTSA1, a pharmacologically optimized BAX activator that binds with high affinity and specificity to the N-terminal activation site and induces conformational changes to BAX leading to BAX-mediated apoptosis. BTSA1-induced BAX activation effectively promotes apoptosis in leukemia cell lines and patient samples while sparing healthy cells. BAX expression levels and cytosolic conformation regulate sensitivity to BTSA1. BTSA1 potently suppressed human acute myeloid leukemia (AML) xenografts and increased host survival without toxicity. This study provides proof-of-concept for direct BAX activation as a treatment strategy in AML.

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“…These family member proteins bind to and functionally neutralize pro-apoptotic BCL-2 family members. Pro-apoptotic BCL-2 proteins activate the BAX and BCL-2 homologous antagonist/killer (BAK) proteins to trigger MOMP, thereby causing cytochrome c release to drive programmed cell death 109 . The senolytic molecules navitoclax and ABT-737 occupy the inhibitory binding grooves of BCL-2, BCL-X L and BCL-W, which counteracts their anti-apoptotic functions and permits SNCs to initiate apoptosis 110 .…”

Section: Therapeutic Targeting Of Sncsmentioning

confidence: 99%

Senescent cells: an emerging target for diseases of ageing

Childs

Gluscevic

Baker

et al. 2017

Nat Rev Drug Discov

944

797

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Chronological age represents the single greatest risk factor for human disease. One plausible explanation for this correlation is that mechanisms that drive ageing might also promote age-related diseases. Cellular senescence, which is a permanent state of cell cycle arrest induced by cellular stress, has recently emerged as a fundamental ageing mechanism that also contributes to diseases of late life, including cancer, atherosclerosis and osteoarthritis. Therapeutic strategies that safely interfere with the detrimental effects of cellular senescence, such as the selective elimination of senescent cells (SNCs) or the disruption of the SNC secretome, are gaining significant attention, with several programmes now nearing human clinical studies.

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Physiological and Pharmacological Control of BAK, BAX, and Beyond

Cited by 133 publications

References 82 publications

Pterostilbene attenuates acute kidney injury in septic mice

Pterostilbene attenuates acute kidney injury in septic mice

Direct Activation of BAX by BTSA1 Overcomes Apoptosis Resistance in Acute Myeloid Leukemia

Senescent cells: an emerging target for diseases of ageing

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