Differential regulation of nuclear and mitochondrial Bcl-2 in T cell apoptosis

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Differential regulation of nuclear and mitochondrial Bcl-2 in T cell apoptosis. / Scheel-Toellner, Dagmar; Raza, Karim; Assi, L; Pilling, Darrell; Ross, Emma; Lee, Wing-Yiu; Curnow, Stephen; Buckley, Christopher; Akbar, AN; Lord, Janet; Salmon, Michael.

In: Apoptosis, Vol. 23, No. 1, 01.01.2008, p. 109-17.

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@article{7af05c6d472a4801ac44a1abe6e13feb,
title = "Differential regulation of nuclear and mitochondrial Bcl-2 in T cell apoptosis",
abstract = "Activated T cells require anti-apoptotic cytokines for their survival. The anti-apoptotic effects of these factors are mediated by their influence on the balance of expression and localisation of pro- and anti-apoptotic members of the Bcl-2 family. Among the anti-apoptotic Bcl-2 family members, the expression level of Bcl-2 itself and its interaction with the pro-apoptotic protein Bim are now regarded as crucial for the regulation of survival in activated T cells. We studied the changes in Bcl-2 levels and its subcellular distribution in relation to mitochondrial depolarisation and caspase activation in survival factor deprived T cells. Intriguingly, the total Bcl-2 level appeared to remain stable, even after caspase 3 activation indicated entry into the execution phase of apoptosis. However, cell fractionation experiments showed that while the dominant nuclear pool of Bcl-2 remained stable during apoptosis, the level of the smaller mitochondrial pool was rapidly downregulated. Signals induced by anti-apoptotic cytokines continuously replenish the mitochondrial pool, but nuclear Bcl-2 is independent of such signals. Mitochondrial Bcl-2 is lost rapidly by a caspase independent mechanism in the absence of survival factors, in contrast only a small proportion of the nuclear pool of Bcl-2 is lost during the execution phase and this loss is a caspase dependent process. We conclude that these two intracellular pools of Bcl-2 are regulated through different mechanisms and only the cytokine-mediated regulation of the mitochondrial pool is relevant to the control of the initiation of apoptosis.",
keywords = "cytokines, lymphocytes, programmed cell death, Bcl-2, survival",
author = "Dagmar Scheel-Toellner and Karim Raza and L Assi and Darrell Pilling and Emma Ross and Wing-Yiu Lee and Stephen Curnow and Christopher Buckley and AN Akbar and Janet Lord and Michael Salmon",
year = "2008",
month = jan,
day = "1",
doi = "10.1007/s10495-007-0143-z",
language = "English",
volume = "23",
pages = "109--17",
journal = "Apoptosis",
issn = "1360-8185",
publisher = "Springer",
number = "1",

}

RIS

TY - JOUR

T1 - Differential regulation of nuclear and mitochondrial Bcl-2 in T cell apoptosis

AU - Scheel-Toellner, Dagmar

AU - Raza, Karim

AU - Assi, L

AU - Pilling, Darrell

AU - Ross, Emma

AU - Lee, Wing-Yiu

AU - Curnow, Stephen

AU - Buckley, Christopher

AU - Akbar, AN

AU - Lord, Janet

AU - Salmon, Michael

PY - 2008/1/1

Y1 - 2008/1/1

N2 - Activated T cells require anti-apoptotic cytokines for their survival. The anti-apoptotic effects of these factors are mediated by their influence on the balance of expression and localisation of pro- and anti-apoptotic members of the Bcl-2 family. Among the anti-apoptotic Bcl-2 family members, the expression level of Bcl-2 itself and its interaction with the pro-apoptotic protein Bim are now regarded as crucial for the regulation of survival in activated T cells. We studied the changes in Bcl-2 levels and its subcellular distribution in relation to mitochondrial depolarisation and caspase activation in survival factor deprived T cells. Intriguingly, the total Bcl-2 level appeared to remain stable, even after caspase 3 activation indicated entry into the execution phase of apoptosis. However, cell fractionation experiments showed that while the dominant nuclear pool of Bcl-2 remained stable during apoptosis, the level of the smaller mitochondrial pool was rapidly downregulated. Signals induced by anti-apoptotic cytokines continuously replenish the mitochondrial pool, but nuclear Bcl-2 is independent of such signals. Mitochondrial Bcl-2 is lost rapidly by a caspase independent mechanism in the absence of survival factors, in contrast only a small proportion of the nuclear pool of Bcl-2 is lost during the execution phase and this loss is a caspase dependent process. We conclude that these two intracellular pools of Bcl-2 are regulated through different mechanisms and only the cytokine-mediated regulation of the mitochondrial pool is relevant to the control of the initiation of apoptosis.

AB - Activated T cells require anti-apoptotic cytokines for their survival. The anti-apoptotic effects of these factors are mediated by their influence on the balance of expression and localisation of pro- and anti-apoptotic members of the Bcl-2 family. Among the anti-apoptotic Bcl-2 family members, the expression level of Bcl-2 itself and its interaction with the pro-apoptotic protein Bim are now regarded as crucial for the regulation of survival in activated T cells. We studied the changes in Bcl-2 levels and its subcellular distribution in relation to mitochondrial depolarisation and caspase activation in survival factor deprived T cells. Intriguingly, the total Bcl-2 level appeared to remain stable, even after caspase 3 activation indicated entry into the execution phase of apoptosis. However, cell fractionation experiments showed that while the dominant nuclear pool of Bcl-2 remained stable during apoptosis, the level of the smaller mitochondrial pool was rapidly downregulated. Signals induced by anti-apoptotic cytokines continuously replenish the mitochondrial pool, but nuclear Bcl-2 is independent of such signals. Mitochondrial Bcl-2 is lost rapidly by a caspase independent mechanism in the absence of survival factors, in contrast only a small proportion of the nuclear pool of Bcl-2 is lost during the execution phase and this loss is a caspase dependent process. We conclude that these two intracellular pools of Bcl-2 are regulated through different mechanisms and only the cytokine-mediated regulation of the mitochondrial pool is relevant to the control of the initiation of apoptosis.

KW - cytokines

KW - lymphocytes

KW - programmed cell death

KW - Bcl-2

KW - survival

U2 - 10.1007/s10495-007-0143-z

DO - 10.1007/s10495-007-0143-z

M3 - Article

C2 - 17957472

VL - 23

SP - 109

EP - 117

JO - Apoptosis

JF - Apoptosis

SN - 1360-8185

IS - 1

ER -