A Role for c-<i>myc</i> in Chemically Induced Renal-Cell Death

Zhan, Yi; Cleveland, John L.; Stevens, James

doi:10.1128/mcb.17.11.6755

Cited by 32 publications

(46 citation statements)

References 63 publications

(87 reference statements)

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“…Each of these mechanisms could prevent a change in [Ca 2ϩ ] i . Renal epithelial LLC-PK 1 cells have been used extensively to investigate cytotoxicity and stress gene activation (11,12,56,60). However, the influence of cell signaling pathways on stress pathways and cell survival during oxidative stress is not well characterized.…”

Section: Discussionmentioning

confidence: 99%

Protection of Renal Epithelial Cells against Oxidative Injury by Endoplasmic Reticulum Stress Preconditioning Is Mediated by ERK1/2 Activation

Hung

Ichimura

Stevens

et al. 2003

Journal of Biological Chemistry

186

134

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We investigated the role of the endoplasmic reticulum (ER) stress response in intracellular Ca 2؉ regulation, MAPK activation, and cytoprotection in LLC-PK 1 renal epithelial cells in an attempt to identify the mechanisms of protection afforded by ER stress. Cells preconditioned with trans-4,5-dihydroxy-1,2-dithiane, tunicamycin, thapsigargin, or A23187 expressed ER stress proteins and were resistant to subsequent H 2 O 2 -induced cell injury. In addition, ER stress preconditioning prevented the increase in intracellular Ca 2؉ concentration that normally follows H 2 O 2 exposure. Stable transfection of cells with antisense RNA targeted against GRP78 (pkASgrp78 cells) prevented GRP78 induction, disabled the ER stress response, sensitized cells to H 2 O 2 -induced injury, and prevented the development of tolerance to H 2 O 2 that normally occurs with preconditioning. ERK and JNK were transiently (30 -60 min) phosphorylated in response to H 2 O 2 . ER stress-preconditioned cells had more ERK and less JNK phosphorylation than control cells in response to H 2 O 2 exposure. Preincubation with a specific inhibitor of JNK activation or adenoviral infection with a construct that encodes constitutively active MEK1, the upstream activator of ERKs, also protected cells against H 2 O 2 toxicity. In contrast, the pkASgrp78 cells had less ERK and more JNK phosphorylation upon H 2 O 2 exposure. Expression of constitutively active ERK also conferred protection on native as well as pkASgrp78 cells. These results indicate that GRP78 plays an important role in the ER stress response and cytoprotection. ER stress preconditioning attenuates H 2 O 2 -induced cell injury in LLC-PK 1 cells by preventing an increase in intracellular Ca 2؉ concentration, potentiating ERK activation, and decreasing JNK activation. Thus, the ER stress response modulates the balance between ERK and JNK signaling pathways to prevent cell death after oxidative injury. Furthermore, ERK activation is an important downstream effector mechanism for cellular protection by ER stress.

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Section: Discussionmentioning

confidence: 99%

Protection of Renal Epithelial Cells against Oxidative Injury by Endoplasmic Reticulum Stress Preconditioning Is Mediated by ERK1/2 Activation

Hung

Ichimura

Stevens

et al. 2003

Journal of Biological Chemistry

186

134

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“…Later studies established that c-Myc was a critical determinant of apoptosis induced by TNF-a (Janicke et al, 1994;Klefstrom et al, 1994;Dong et al, 1997) and of the magnitude of the response to ligation of the CD95/ Fas death receptor (Hueber et al, 1997). However, it now appears that c-Myc is required for e cient response to a variety of apoptotic stimuli, including transcription and translation inhibitors, hypoxia, glucose deprival, heat shock, chemotoxins, DNA damage, and cancer chemotherapeutics Harrington et al, 1994a;Wagner et al, 1994;Yao et al, 1995;Alarcon et al, 1996;Graeber et al, 1996;Jiang et al, 1996;Kang et al, 1996;Li et al, 1996;Dong et al, 1997;Koumenis and Giaccia, 1997;Zhan et al, 1997;Nesbit et al, 1998;Rupnow et al, 1998;Shim et al, 1998). Evan and Littlewood have proposed the appealing idea that c-Myc does not act as a death e ector in all these instances but instead acts to sensitize cells to a variety of apoptotic triggers (Evan and Littlewood, 1998).…”

Section: C-myc Induces Apoptosismentioning

confidence: 99%

“…Signi®cantly, ODC has been shown to be necessary and su cient for apoptosis by c-Myc in 32D myeloid cells (Packham and Cleveland, 1994). ODC does not drive cell death nearly as e ciently as c-Myc but in support of its role it has been reported to be an important participant with c-Myc in chemotoxin-induced cell death (Zhan et al, 1997). ODC is a housekeeping enzyme involved in polyamine synthesis and is necessary for cell proliferation.…”

Section: Myc Target Genes and Apoptosismentioning

confidence: 99%

Mechanisms of apoptosis by c-Myc

1999

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“…Cells were treated with various concentrations of DCVC for the indicated times. All incubations were performed in the presence of 20 M DPPD (10 mM stock in dimethyl sulfoxide) to block the oxidative stress-dependent necrotic pathway but allowing for the onset of apoptosis (22,34).…”

Section: Methodsmentioning

confidence: 99%

“…Cells-To investigate the activation of p38 and JNK in relation to chemically induced injury of renal proximal tubular epithelial cells, LLC-PK1 cells were treated with the model nephrotoxicant DCVC that causes apoptosis of renal epithelial cells in a ␤-lyase-dependent manner (22,34). The induction of apoptosis (Fig.…”

Section: Activation Of Stress Kinases P38 and Jnk Precedes Nephrotoximentioning

confidence: 99%

Heat Shock Protein 27 Is the Major Differentially Phosphorylated Protein Involved in Renal Epithelial Cellular Stress Response and Controls Focal Adhesion Organization and Apoptosis

Graauw

Tijdens

Cramer

et al. 2005

Journal of Biological Chemistry

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We used two-dimensional difference gel electrophoresis to determine early changes in the stress-response pathways that precede focal adhesion disorganization linked to the onset of apoptosis of renal epithelial cells. Treatment of LLC-PK1 cells with the model nephrotoxicant 1,2-(dichlorovinyl)-L-cysteine (DCVC) resulted in a >1.5-fold up-and down-regulation of 14 and 9 proteins, respectively, preceding the onset of apoptosis. Proteins included those involved in metabolism, i.e. aconitase and pyruvate dehydrogenase, and those related to stress responses and cytoskeletal reorganization, i.e. cofilin, Hsp27, and ␣-b-crystallin. The most prominent changes were found for Hsp27, which was related to a pI shift in association with an altered phosphorylation status of serine residue 82. Although both p38 and JNK were activated by DCVC, only inhibition of p38 with SB203580 reduced Hsp27 phosphorylation, which was associated with accelerated reorganization of focal adhesions, cell detachment, and apoptosis. In contrast, inhibition of JNK with SP600125 maintained cell adhesion as well as protection against apoptosis. Active JNK co-localized at focal adhesions after DCVC treatment in a FAK-dependent manner. Inhibition of active JNK localization at focal adhesions did not prevent DCVC-induced phosphorylation of Hsp27. Overexpression of a phosphorylationdefective mutant Hsp27 acted as a dominant negative and accelerated the DCVC-induced changes in the focal adhesions as well as the onset of apoptosis. Our data fit a model whereby early p38 activation results in a rapid phosphorylation of Hsp27, a requirement for proper maintenance of cell adhesion, thus suppressing renal epithelial cell apoptosis.

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A Role for c-myc in Chemically Induced Renal-Cell Death

Cited by 32 publications

References 63 publications

Protection of Renal Epithelial Cells against Oxidative Injury by Endoplasmic Reticulum Stress Preconditioning Is Mediated by ERK1/2 Activation

Protection of Renal Epithelial Cells against Oxidative Injury by Endoplasmic Reticulum Stress Preconditioning Is Mediated by ERK1/2 Activation

Mechanisms of apoptosis by c-Myc

Heat Shock Protein 27 Is the Major Differentially Phosphorylated Protein Involved in Renal Epithelial Cellular Stress Response and Controls Focal Adhesion Organization and Apoptosis

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