Expression of Bcl-2 Increases Intracellular Glutathione by Inhibiting Methionine-Dependent GSH Efflux

Meredith, Michael; Cusick, Carrie L.; Soltaninassab, Syrus R.; Sekhar, Konjeti S.; Lu, Shelly C.; Freeman, Michael L.

doi:10.1006/bbrc.1998.8998

Cited by 88 publications

(57 citation statements)

References 46 publications

(16 reference statements)

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“…From the original observation of the importance of GSH on the ability of BCL-2 to suppress apoptosis, ample evidence has accumulated regarding a positive correlation between GSH and BCL-2. 4,[47][48][49][50][51][52][53][54][55] Our data confirm the correlation between GSH and BCL-2 in our model system. In addition, accumulation of GSH in the presence of BCL-2 has been observed in bacteria when OxyR transcription factor can be activated by disulfide formation.…”

Section: Bcl-2 Inhibits Formation Of Reactive Oxygen Species 359supporting

confidence: 82%

BCL-2 is involved in preventing oxidant-induced cell death and in decreasing oxygen radical production

Amstad

Liu

Ichimiya³

et al. 2001

Redox Report

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Section: Bcl-2 Inhibits Formation Of Reactive Oxygen Species 359supporting

confidence: 82%

BCL-2 is involved in preventing oxidant-induced cell death and in decreasing oxygen radical production

Amstad

Liu

Ichimiya³

et al. 2001

Redox Report

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“…The apparent mechanism by which Bcl-2 inhibits oxidative damage during apoptosis varies among cell types and remains unclear in some cases. In Bcl-2-transfected HeLa, Bcl-2 may act by increasing basal glutathione levels (41). Intrahepatic cholangiocytes express high levels of Bcl-2, unlike most other cell types in vivo (25).…”

Section: Discussionmentioning

confidence: 99%

Bcl-2–dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis

Odin¹,

Huebert²,

Casciola‐Rosen³

et al. 2001

J. Clin. Invest.

101

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The close association between autoantibodies against pyruvate dehydrogenase-E2 (PDC-E2), a ubiquitous mitochondrial protein, and primary biliary cirrhosis (PBC) is unexplained. Many autoantigens are selectively modified during apoptosis, which has focused attention on apoptotic cells as a potential source of "neo-antigens" responsible for activating autoreactive lymphocytes. Since increased apoptosis of bile duct epithelial cells (cholangiocytes) is evident in patients with PBC, we evaluated the effect of apoptosis on PDC-E2. Autoantibody recognition of PDC-E2 by immunofluorescence persisted in apoptotic cholangiocytes and appeared unchanged by immunoblot analysis. PDC-E2 was neither cleaved by caspases nor concentrated into surface blebs in apoptotic cells. In other cell types, autoantibody recognition of PDC-E2, as assessed by immunofluorescence, was abrogated after apoptosis, although expression levels of PDC-E2 appeared unchanged when examined by immunoblot analysis. Both overexpression of Bcl-2 and depletion of glutathione before inducing apoptosis prevented this loss of autoantibody recognition, suggesting that glutathiolation, rather than degradation or loss, of PDC-E2 was responsible for the loss of immunofluorescence signal. We postulate that apoptotic cholangiocytes, unlike other apoptotic cell types, are a potential source of immunogenic PDC-E2 in patients with PBC.

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“…Effects of Bcl-2 on cellular glutathione have already been described for a variety of other cell types, although they were not considered with respect to cellular Ca# + homoeostasis [13][14][15][16][17][18]. Despite these data on Bcl-2 and glutathione, little is known to date about the precise mechanism by which Bcl-2 alters cellular glutathione metabolism.…”

Section: Bcl-2 and Cellular Glutathionementioning

confidence: 99%

“…However, neither of these protective mechanisms can explain the fact that the basal level of GSH was itself markedly increased in the Bcl-2-transfected cells. Since this high level of GSH appears to contribute substantially to the increased resistance of the Rat-1\Bcl-2 cells, direct effects of Bcl-2 on glutathione metabolism, such as inhibition of a methioninedependent GSH efflux [15], are the more likely explanation for the protection exerted by this oncogene on H # O # cytotoxicity to the Rat-1 fibroblasts. Further investigations, however, are needed to support this assumption, but what seems to be clear from the present study is that, in a model of massive, external oxidative stress induction, Bcl-2 influences intracellular Ca# + fluxes only indirectly by increasing the GSH-dependent antioxidative capacity of the cell.…”

Section: Bcl-2 and Cellular Glutathionementioning

confidence: 99%

“…The effects reported include up-regulation of cellular GSH, increased resistance to apoptosis due to a reductive shift of the cellular oxidation-reduction potential and redistribution of GSH to the nucleus and thus protection against DNA fragmentation [13][14][15][16][17][18]. Unfortunately, however, in these studies on Bcl-2 and GSH, no consideration has been given to cellular Ca# + homoeostasis, although, in several models of cell Abbreviations used : BSO, DL-buthionine-(S,R)-sulphoximine ; DTPA, diethylenetriaminepenta-acetic acid ; LDH, lactate dehydrogenase ; quin-2-AM and fura-2-AM, acetoxymethyl esters of quin-2 and fura-2 ; HBSS, Hanks' balanced salt solution ; ' glutathione ' is used where the oxidation state (GSH or GSSG) is not specified.…”

Section: Introductionmentioning

confidence: 99%

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Protection against hydrogen peroxide cytotoxicity in Rat-1 fibroblasts provided by the oncoprotein Bcl-2: maintenance of calcium homoeostasis is secondary to the effect of Bcl-2 on cellular glutathione

Rimpler

Rauen

Schmidt

et al. 1999

Biochemical Journal

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The oncoprotein Bcl-2 protects cells against apoptosis, but the exact molecular mechanism that underlies this function has not yet been identified. Studying H2O2-induced cell injury in Rat-1 fibroblast cells, we observed that Bcl-2 had a protective effect against the increase in cytosolic calcium concentration and subsequent cell death. Furthermore, overexpression of Bcl-2 resulted in an alteration of cellular glutathione status: the total amount of cellular glutathione was increased by about 60% and the redox potential of the cellular glutathione pool was maintained in a more reduced state during H2O2 exposure compared with non-Bcl-2-expressing controls. In our cytotoxicity model, disruption of cellular glutathione homoeostasis closely correlated with the pathological elevation of cytosolic calcium concentration. Stabilization of the glutathione pool by Bcl-2, N-acetylcysteine or glucose delayed the cytosolic calcium increase and subsequent cell death, whereas depletion of glutathione by DL-buthionine-(S,R)-sulphoximine, sensitized Bcl-2-transfected cells towards cytosolic calcium increase and cell death. We therefore suggest that the protection exerted by Bcl-2 against H2O2-induced cytosolic calcium elevation and subsequent cell death is secondary to its effect on the cellular glutathione metabolism.

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Expression of Bcl-2 Increases Intracellular Glutathione by Inhibiting Methionine-Dependent GSH Efflux

Cited by 88 publications

References 46 publications

BCL-2 is involved in preventing oxidant-induced cell death and in decreasing oxygen radical production

BCL-2 is involved in preventing oxidant-induced cell death and in decreasing oxygen radical production

Bcl-2–dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis

Protection against hydrogen peroxide cytotoxicity in Rat-1 fibroblasts provided by the oncoprotein Bcl-2: maintenance of calcium homoeostasis is secondary to the effect of Bcl-2 on cellular glutathione

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