BCL-xL overexpression effectively protects against tetrafluoroethylcysteine-induced intramitochondrial damage and cell death

Ho, Han Kiat; Hu, Zhong Hua; Tzung, Shie-Pon; Hockenbery, David M.; Fausto, Nelson; Nelson, Sidney D.; Bruschi, Sam A.

doi:10.1016/j.bcp.2004.08.030

Cited by 12 publications

(18 citation statements)

References 49 publications

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“…24,25 Indeed, infection of cells with Adv-Bcl-xL (10 or 15 mois for 48 hours) markedly increased Bcl-xL protein abundance and fully protected VSMCs against rMfn-2-induced activation of caspase-9 ( Figure 7E). This protective effect was also confirmed by Cell Death ELISA ( Figure 7F).…”

Section: Adenoviral Gene Transfer Of Bcl-xl Abolishes Rmfn-2-induced mentioning

confidence: 94%

“…Bax insertion into the mitochondrial membrane causes release of cytochrome c, resulting in cellular apoptosis, 3 whereas Bcl-2 blocks mitochondrial cytochrome c release and thus prevents subsequent activation of caspase-9 and caspase-3. 24,25 Here, we have shown that the rMfn-2 apoptotic effect is mediated by the mitochondrial apoptotic pathway, because rMfn-2 profoundly decreases the level of mitochondrial antiapoptotic protein Bcl-2, while increasing Bax mitochondrial accumulation, resulting in mitochondrial cytochrome c release and activation of caspase-9 and caspase-3 but not caspase-8. Moreover, inhibition of caspase-9 or overexpression of the mitochondrial antiapoptotic protein Bcl-xL is able to abolish the apoptotic effect of rMfn-2.…”

Section: Molecular Mechanism Underlying Rmfn-2-mediated Apoptosismentioning

confidence: 94%

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Mitofusin 2 Triggers Vascular Smooth Muscle Cell Apoptosis via Mitochondrial Death Pathway

Guo

Chen

Guo

et al. 2007

Circulation Research

173

136

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Abstract-Previous studies have shown that mitofusin 2 (Mfn-2) (or hyperplasia suppressor gene [HSG]) inhibits vascular smooth muscle cell (VSMC) proliferation. Here, we demonstrate that Mfn-2 is a primary determinant of VSMC apoptosis. First, oxidative stress with H 2 O 2 , inhibition of protein kinase C with staurosporine, activation of protein kinase A with forskolin, and serum deprivation concurrently elevate Mfn-2 expression and induce VSMC apoptosis. Second, overexpression of Mfn-2 also triggers apoptosis of VSMCs in culture and in balloon-injured rat carotid arteries, thus contributing to Mfn-2-mediated prevention of neointima formation after angioplasty. Third, Mfn-2 silencing protects VSMCs against H 2 O 2 or Mfn-2 overexpression-induced apoptosis, indicating that upregulation of Mfn-2 is necessary and sufficient for oxidative stress-mediated VSMC apoptosis. The Mfn-2 proapoptotic effect is independent of its role in mitochondrial fusion but mainly mediated by inhibition of Akt signaling and the resultant activation of the mitochondrial apoptotic pathway, as manifested by decreased Akt phosphorylation, increased mitochondrial Bax/Bcl-2 ratio, cytochrome c release, and activation of caspases-9 and caspase-3. Furthermore, Mfn-2-induced apoptosis was blocked by overexpression of an active phosphoinositide 3-kinase mutant or Bcl-xL or inhibition of caspase-9 but not caspases-8. Key Words: PI3K-Akt Ⅲ apoptosis Ⅲ HSG Ⅲ Mfn-2 Ⅲ vascular smooth muscle cells A poptosis is a programmed cell death that is essential for embryonic development and for tissue homeostasis, remodeling, and immune responses. There are 2 major apoptotic signaling cascades: the first is the death receptor (Fas or tumor necrosis factor receptor)-mediated pathway involving activation of caspase-8 and its downstream executioner caspases; the other is the mitochondrial pathway activated by cellular deprivation or stress, and it involves sequentially the release of cytochrome c, the recruitment of apoptotic protease activating factor-1 (Apaf-1), and the activation of caspase-9 and downstream executioner caspases. [1][2][3] Defects (inhibition or exacerbation) of either pathway trigger proliferative or degenerative disorders, including atherosclerosis, restenosis, myocardial infarction, cancers, neurodegenerative diseases, and AIDS. [3][4][5][6][7] Ras, a small GTPase, plays a central role in the regulation of many fundamental biological processes, such as cell proliferation, differentiation, senescence, survival, and growth via activation of a wide array of downstream signaling pathways. Among them, the Ras-Raf-MEK-ERK/ mitogen-activated protein kinase (MAPK) pathway and the Ras-PI3K-Akt (also known as protein kinase [PK]B) pathway are vital for cell proliferation and cell survival. 8 -11 Whereas the Ras-MAPK pathway drives cell cycle progression, 9 the activation of the Ras-PI3K-Akt signaling blocks apoptotic cell death. 11 In particular, Akt-mediated phosphorylation of proapoptotic members of the Bcl-2 family, including Bad and Bax, prevents ...

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Section: Adenoviral Gene Transfer Of Bcl-xl Abolishes Rmfn-2-induced mentioning

confidence: 94%

Section: Molecular Mechanism Underlying Rmfn-2-mediated Apoptosismentioning

confidence: 94%

Mitofusin 2 Triggers Vascular Smooth Muscle Cell Apoptosis via Mitochondrial Death Pathway

Guo

Chen

Guo

et al. 2007

Circulation Research

173

136

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“…In TAMH, sensitivity to Tgf β 1-induced cell death is regulated by the level of Bcl-xL protein that is expressed. Overexpression of Bcl-xL was shown to prevent Tgf β 1-induced apoptosis by inhibiting caspase activity and cell death, leading to the observation that Bcl-xL overexpression correlates highly with cell viability [12]. The overexpression of Bcl-xL in TAMH is believed to shift energy utilization from oxidative phosphorylation to glycolysis, and acute inhibition of cells overexpressing Bcl-xl led to progressive mitochondrial accumulation of reduced NAD(P)H and the generation of reactive oxygen species (ROS) [13].…”

Section: Pathwaysmentioning

confidence: 99%

“…This was associated with an early endoplasmic reticular (ER) stress response and time dependent upregulation of ER-response genes, suggesting a potential alternative pathway for Nrf2 phosphorylation through ER-mediated protein kinases [56]. Lastly, Bcl-xL overexpression, which led to the suppression of Bax movement to the mitochondria, protected against TFEC-induced injury (Figure 1(b)) [12]. TFEC exposure also led to a unique HSP regulation profile [55].…”

Section: Agentsmentioning

confidence: 99%

TAMH: A Useful In Vitro Model for Assessing Hepatotoxic Mechanisms

Davis

Stamper

2016

BioMed Research International

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In vitro models for hepatotoxicity can be useful tools to predict in vivo responses. In this review, we discuss the use of the transforming growth factor-α transgenic mouse hepatocyte (TAMH) cell line, which is an attractive model to study drug-induced liver injury due to its ability to retain a stable phenotype and express drug-metabolizing enzymes. Hepatotoxicity involves damage to the liver and is often associated with chemical exposure. Since the liver is a major site for drug metabolism, drug-induced liver injury is a serious health concern for certain agents. At the molecular level, various mechanisms may protect or harm the liver during drug-induced hepatocellular injury including signaling pathways and endogenous factors (e.g., Bcl-2, GSH, Nrf2, or MAPK). The interplay between these and other pathways in the hepatocyte can change upon drug or drug metabolite exposure leading to intracellular stress and eventually cell death and liver injury. This review focuses on mechanistic studies investigating drug-induced toxicity in the TAMH line and how alterations to hepatotoxic mechanisms in this model relate to the in vivo situation. The agents discussed herein include acetaminophen (APAP), tetrafluoroethylcysteine (TFEC), flutamide, PD0325901, lapatinib, and flupirtine.

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“…Caspase-3 activities were determined by incubating cell lysates at 37°C in caspase assay buffer as described previously [26]. Fluorescence was by the release of hydrolyzed AMC substrates detected with excitation/ emission wavelengths = 380/450 nm.…”

Section: Caspase-3 Activity Assaymentioning

confidence: 99%

Fibroblast growth factor receptor 4 regulates proliferation, anti-apoptosis and alpha-fetoprotein secretion during hepatocellular carcinoma progression and represents a potential target for therapeutic intervention

Pok

Streit

et al. 2009

Journal of Hepatology

164

152

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BCL-xL overexpression effectively protects against tetrafluoroethylcysteine-induced intramitochondrial damage and cell death

Cited by 12 publications

References 49 publications

Mitofusin 2 Triggers Vascular Smooth Muscle Cell Apoptosis via Mitochondrial Death Pathway

Mitofusin 2 Triggers Vascular Smooth Muscle Cell Apoptosis via Mitochondrial Death Pathway

TAMH: A Useful In Vitro Model for Assessing Hepatotoxic Mechanisms

Fibroblast growth factor receptor 4 regulates proliferation, anti-apoptosis and alpha-fetoprotein secretion during hepatocellular carcinoma progression and represents a potential target for therapeutic intervention

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