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Mcl-1 and Bcl-xL sequestration of Bak confers differential resistance to BH3-only proteins.

ABSTRACT: The prosurvival Bcl-2 family proteins Mcl-1 and Bcl-xL inhibit apoptosis by sequestering BH3-only proteins such as Bid and Bim (MODE 1) or the effector proteins Bak and Bax (MODE 2). To better understand the contributions of MODE 1 and MODE 2 in blocking cell death, and thus how to bypass resistance to cell death, we examined prescribed mixtures of Bcl-2 family proteins. In a Bim and Bak mixture, Bcl-xL and Mcl-1 each sequestered not only Bim but also Bak as it became activated by Bim. In contrast, in a Bid and Bak mixture, Bcl-xL preferentially sequestered Bid while Mcl-1 preferentially sequestered Bak. Notably, Bcl-xL could sequester Bak in response to the BH3 mimetic ABT-737, despite this molecule targeting Bcl-xL. These findings highlight the importance of Bak sequestration in resistance to anti-cancer treatments, including BH3 mimetics.

SUBMITTER: Hockings C

PROVIDER: S-EPMC5864222 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Mcl-1 and Bcl-xL sequestration of Bak confers differential resistance to BH3-only proteins.

Hockings Colin C Alsop Amber E AE Fennell Stephanie C SC Lee Erinna F EF Fairlie W Douglas WD Dewson Grant G Kluck Ruth M RM

Cell death and differentiation 20180219 4

The prosurvival Bcl-2 family proteins Mcl-1 and Bcl-xL inhibit apoptosis by sequestering BH3-only proteins such as Bid and Bim (MODE 1) or the effector proteins Bak and Bax (MODE 2). To better understand the contributions of MODE 1 and MODE 2 in blocking cell death, and thus how to bypass resistance to cell death, we examined prescribed mixtures of Bcl-2 family proteins. In a Bim and Bak mixture, Bcl-xL and Mcl-1 each sequestered not only Bim but also Bak as it became activ ...[more]

PMID: 29459767

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Project description:BACKGROUND: Delayed neutrophil apoptosis may be an important factor in the persistent inflammation associated with chronic obstructive pulmonary disease (COPD). Bcl-2 family proteins are important regulators of neutrophil apoptosis. We determined the mRNA levels of pro-apoptotic Bak and anti-aptototic Bcl-xl and Mcl-1 members of the Bcl-2 family in unstimulated peripheral blood neutrophils from patients with mild to moderate COPD and compared these to neutrophils from healthy controls. METHODS: Neutrophils were isolated from peripheral blood samples of 47 COPD patients (smokers: N?=?24) and 47 healthy controls (smokers: N?=?24). Percentages of apoptotic cells were determined at 4, 24, and 36 h for unstimulated neutrophils cultured in vitro. Neutrophil mRNA expression of Bak, Bcl-xl, and Mcl-1 was determined by real-time polymerase chain reaction (PCR). FEV1 (% predicted) and FVC were determined by spirometry and correlations between mRNA levels and lung function parameters were determined. RESULTS: The percentages of apoptotic cells among unstimulated neutrophils from COPD patients were significantly lower compared to cells from controls after 4, 24, and 36 h in culture; smoking history had only a minimal effect on these differences. Unstimulated neutrophils from COPD patients had significantly lower Bak mRNA expression and higher expressions of Bcl-xl and Mcl-1 mRNA than cells from healthy controls. Again, smoking history had only a minimal effect on these trends. Bak mRNA expression was significantly positively correlated with both % predicted FEV1 and the FEV1/FVC ratio, while Bcl-xl and Mcl-1 mRNA expressions were significantly negatively correlated with %predicted FEV1 and the FEV1/FVC ratio. CONCLUSIONS: The genes for pro-apoptotic Bak, and anti-apoptotic Bcl-xl and Mcl-1 may be important in regulating the delayed neutrophil apoptosis observed in COPD, which may contribute to COPD pathogenesis. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1605269445677066.

Dataset Information

Mcl-1 and Bcl-xL sequestration of Bak confers differential resistance to BH3-only proteins.

Publications

Mcl-1 and Bcl-x<sub>L</sub> sequestration of Bak confers differential resistance to BH3-only proteins.

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