Myc Potentiates Apoptosis by Stimulating Bax Activity at the Mitochondria

ABSTRACT The ability of the c-Myc oncoprotein to potentiate apoptosis has been well documented; however, the mechanism of action remains ill defined. We have previously identified spatially distinct apoptotic pathways within the same cell that are differentially inhibited by Bcl-2 targeted to either the mitochondria (Bcl-acta) or the endoplasmic reticulum (Bcl-cb5). We show here that in Rat1 cells expressing an exogenous c-myc allele, distinct apoptotic pathways can be inhibited by Bcl-2 or Bcl-acta yet be distinguished by their sensitivity to Bcl-cb5 as either susceptible (serum withdrawal, taxol, and ceramide) or refractory (etoposide and doxorubicin). Myc expression and apoptosis were universally associated with Bcl-acta and not Bcl-cb5, suggesting that Myc acts downstream at a point common to these distinct apoptotic signaling cascades. Analysis of Rat1 c-myc null cells shows these same death stimuli induce apoptosis with characteristic features of nuclear condensation, membrane blebbing, poly (ADP-ribose) polymerase cleavage, and DNA fragmentation; however, this Myc-independent apoptosis is not inhibited by Bcl-2. During apoptosis, Bax translocation to the mitochondria occurs in the presence or absence of Myc expression. Moreover, Bax mRNA and protein expression remain unchanged in the presence or absence of Myc. However, in the absence of Myc, Bax is not activated and cytochrome c is not released into the cytoplasm. Reintroduction of Myc into the c-myc null cells restores Bax activation, cytochrome c release, and inhibition of apoptosis by Bcl-2. These results demonstrate a role for Myc in the regulation of Bax activation during apoptosis. Moreover, apoptosis that can be triggered in the absence of Myc provides evidence that signaling pathways exist which circumvent Bax activation and cytochromec release to trigger caspase activation. Thus, Myc increases the cellular competence to die by enhancing disparate apoptotic signals at a common mitochondrial amplification step involving Bax activation and cytochrome c release.

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Faculty Opinions recommendation of The KDEL receptor modulates the endoplasmic reticulum stress response through mitogen-activated protein kinase signaling cascades.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718877833.793499944 ◽

2014 ◽

Author(s):

Alberto Luini

Keyword(s):

Endoplasmic Reticulum ◽

Stress Response ◽

Protein Kinase ◽

Endoplasmic Reticulum Stress ◽

Mitogen Activated Protein Kinase ◽

Signaling Cascades ◽

Endoplasmic Reticulum Stress Response ◽

Mitogen Activated Protein ◽

Protein Kinase Signaling ◽

Kdel Receptor

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Aromadendrin Protects Neuronal Cells from Methamphetamine-Induced Neurotoxicity by Regulating Endoplasmic Reticulum Stress and PI3K/Akt/mTOR Signaling Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms22052274 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2274

Author(s):

Hyun-Su Lee ◽

Eun-Nam Kim ◽

Gil-Saeng Jeong

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Signaling Pathway ◽

Neuronal Cells ◽

Mammalian Target Of Rapamycin ◽

Mtor Signaling ◽

Mtor Signaling Pathway ◽

Irreversible Damage ◽

Pre Treatment ◽

Apoptotic Pathways

Methamphetamine (METH) is a highly addictive drug that induces irreversible damage to neuronal cells and pathological malfunction in the brain. Aromadendrin, isolated from the flowers of Chionanthus retusus, has been shown to have anti-inflammatory or anti-tumor activity. Nevertheless, it has been reported that METH exacerbates neurotoxicity by inducing endoplasmic reticulum (ER) stress via the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway in neuronal cells. There is little evidence that aromadendrin protects cells from neurotoxicity induced by METH. In this study, we found that aromadendrin partially suppressed the METH-induced cell death in SH-SY5y cells without causing cytotoxicity. Aromadendrin regulated METH-induced ER stress by preserving the phosphorylation of the PI3K/Akt/mTOR signaling pathway in METH-exposed SH-SY5y cells. In addition, aromadendrin mitigated METH-induced autophagic and the apoptotic pathways in METH-exposed SH-SY5y cells. Mechanistic studies revealed that pre-treatment with aromadendrin restored the expression of anti-apoptotic proteins in METH-exposed conditions. The inhibitor assay confirmed that aromadendrin-mediated restoration of mTOR phosphorylation protected cells from autophagy and apoptosis in METH-exposed cells. Therefore, these findings suggest that aromadendrin relatively has a protective effect on SH-SY5y cells against autophagy and apoptosis induced by METH via regulation of ER stress and the PI3K/Akt/mTOR signaling pathway.

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Delayed activation of caspase-independent apoptosis during heart failure in transgenic mice overexpressing caspase inhibitor CrmA

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00168.2010 ◽

2010 ◽

Vol 299 (5) ◽

pp. H1374-H1381 ◽

Cited By ~ 16

Author(s):

Soochan Bae ◽

Parco M. Siu ◽

Sangita Choudhury ◽

Qingen Ke ◽

Jun H. Choi ◽

...

Keyword(s):

Heart Failure ◽

Caspase Inhibitor ◽

Wild Type ◽

Caspase Activation ◽

Response Modifier ◽

Specific Expression ◽

Caspase Inhibition ◽

Cardiac Apoptosis ◽

Apoptotic Pathways ◽

Apoptosis Inducing Factor

Although caspase activation is generally thought to be necessary to induce apoptosis, recent evidence suggests that apoptosis can be activated in the setting of caspase inhibition. In this study, we tested the hypothesis that caspase-independent apoptotic pathways contribute to the development of heart failure in the absence of caspase activation. Acute cardiomyopathy was induced using a single dose of doxorubicin (Dox, 20 mg/kg) injected into male wild-type (WT) and transgenic (Tg) mice with a cardiac-specific expression of cytokine response modifier A (CrmA), a known caspase inhibitor. Early (6 day) survival was significantly better in CrmA Tg (81%) than WT (38%) mice. Twelve days after Dox injection, however, the mortality benefit had dissipated, and increased cardiac apoptosis was observed in both groups. There was, however, a significantly greater release of apoptosis-inducing factor (AIF) from mitochondria to cytosol in CrmA Tg compared with WT mice, which suggests that an enhancement of activation in caspase-independent apoptotic pathways had occurred. The administration of a poly(ADP-ribose) polymerase-1 inhibitor, 4-amino-1,8-naphthalimide (4-AN), to Dox-treated mice resulted in significantly improved cardiac function, a significant blockade of AIF released from mitochondria, and decreased cardiac apoptosis. There were also significantly improved survival in WT (18% without 4-AN vs. 89% with 4-AN) and CrmA Tg (13% without 4-AN vs. 93% with 4-AN) mice 12 days after Dox injection. In conclusion, these findings suggest that apoptosis can be induced in the heart lacking caspase activation via caspase-independent pathways and that enabling the inhibition of AIF activation may provide a significant cardiac benefit.

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The Induction of Apoptosis in A375 Malignant Melanoma Cells bySutherlandia frutescens

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/4921067 ◽

2016 ◽

Vol 2016 ◽

pp. 1-14 ◽

Cited By ~ 5

Author(s):

Nicola B. van der Walt ◽

Zahra Zakeri ◽

Marianne J. Cronjé

Keyword(s):

Malignant Melanoma ◽

Basic Mechanism ◽

Melanoma Cells ◽

Caspase Activation ◽

Nuclear Condensation ◽

Induced Apoptosis ◽

Apoptosis Inducing Factor ◽

A375 Melanoma Cell Line ◽

A375 Cells

Sutherlandia frutescensis a medicinal plant indigenous to Southern Africa and is commonly known as the “cancer bush.” This plant has traditionally been used for the treatment of various ailments, although it is best known for its claims of activity against “internal” cancers. Here we report on its effect on melanoma cells. The aim of this study was to investigate whether an extract ofS. frutescenscould induce apoptosis in the A375 melanoma cell line and to outline the basic mechanism of action.S. frutescensextract induced apoptosis in A375 cells as evidenced by morphological features of apoptosis, phosphatidylserine exposure, nuclear condensation, caspase activation, and the release of cytochromecfrom the mitochondria. Studies in the presence of a pan-caspase inhibitor allude to caspase-independent cell death, which appeared to be mediated by the apoptosis inducing factor. Taken together, the results of this study show thatS. frutescensextract is effective in inducing apoptosis in malignant melanoma cells and indicates that furtherin vivomechanistic studies may be warranted.

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Cinacalcet improves bone parameters through regulation of osteoclast endoplasmic reticulum stress, autophagy, and apoptotic pathways in chronic kidney disease‐mineral and bone disorder

Journal of Bone and Mineral Research ◽

10.1002/jbmr.4459 ◽

2021 ◽

Author(s):

Hui‐Wen Chiu ◽

Yi‐Chou Hou ◽

Chien‐Lin Lu ◽

Kuo‐Cheng Lu ◽

Wen‐Chih Liu ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Endoplasmic Reticulum ◽

Kidney Disease ◽

Endoplasmic Reticulum Stress ◽

Mineral And Bone Disorder ◽

Bone Parameters ◽

Bone Disorder ◽

Apoptotic Pathways

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Peroxide-induced membrane blebbing in endothelial cells associated with glutathione oxidation but not apoptosis

AJP Cell Physiology ◽

10.1152/ajpcell.1999.277.1.c20 ◽

1999 ◽

Vol 277 (1) ◽

pp. C20-C28 ◽

Cited By ~ 34

Author(s):

Roosje M. A. van Gorp ◽

Jos L. V. Broers ◽

Chris P. M. Reutelingsperger ◽

Nancy M. H. J. Bronnenberg ◽

Gerard Hornstra ◽

...

Keyword(s):

Endothelial Cells ◽

Early Stage ◽

Morphological Changes ◽

Reductase Activity ◽

Umbilical Vein ◽

Cell Types ◽

Surface Expression ◽

Nuclear Condensation ◽

Membrane Blebbing ◽

Bleb Formation

Cells under oxidative stress induced by peroxides undergo functional and morphological changes, which often resemble those observed during apoptosis. Peroxides, however, also cause the oxidation of intracellular reduced glutathione (GSH). We investigated the relation between these peroxide-induced effects by using human umbilical vein endothelial cells (HUVEC) and two HUVEC-derived cell lines, ECRF24 and ECV304. With HUVEC, tert-butyl hydroperoxide ( tBH) or hydrogen peroxide application in the presence of serum induced, in a dose-dependent way, reorganization of the actin cytoskeleton, membrane blebbing, and nuclear condensation. These processes were accompanied by transient oxidation of GSH. With ECRF24 cells, this treatment resulted in less blebbing and a shorter period of GSH oxidation. However, repeated tBH addition increased the number of blebbing cells and prolonged the period of GSH oxidation. ECV304 cells were even more resistant to peroxide-induced bleb formation and GSH oxidation. Inhibition of glutathione reductase activity potentiated the peroxide-induced blebbing response in HUVEC and ECRF24 cells, but not in ECV304 cells. Neither membrane blebbing nor nuclear condensation in any of these cell types was due to apoptosis, as evidenced by the absence of surface expression of phosphatidylserine or fragmentation of DNA, even after prolonged incubations with tBH, although high tBH concentrations lead to nonapoptotic death. We conclude that, in endothelial cells, peroxide-induced cytoskeletal reorganization and bleb formation correlate with the degree of GSH oxidation but do not represent an early stage of the apoptotic process.

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