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Figure.
The genes listed in the Table predict a molecular system that enables glioma cells to resist oxidative and endoplasmic reticulum (ER) stress. Genes that are up-regulated in glioma cells compared with normal brain tissue are shown in red. Inhibitory and stimulatory (facilitating) “interactions” are depicted as cyan and orange, respectively. Double arrows indicate translocation or binding. Double green lines depict the plasma membrane. Double brown lines depict the mitochondrial membrane. PERK indicates double-stranded RNA-dependent protein kinase–like ER kinase or pancreatic ER kinase.

The genes listed in the Table predict a molecular system that enables glioma cells to resist oxidative and endoplasmic reticulum (ER) stress. Genes that are up-regulated in glioma cells compared with normal brain tissue are shown in red. Inhibitory and stimulatory (facilitating) “interactions” are depicted as cyan and orange, respectively. Double arrows indicate translocation or binding. Double green lines depict the plasma membrane. Double brown lines depict the mitochondrial membrane. PERK indicates double-stranded RNA-dependent protein kinase–like ER kinase or pancreatic ER kinase.

Table. 
Genes Relevant to the Phenotype of Resistance to Oxidative and Endoplasmic Reticulum Stresses Discovered to Be Up-regulated in Cultured Glioma Cells Compared With Normal Brain Tissue
Genes Relevant to the Phenotype of Resistance to Oxidative and Endoplasmic Reticulum Stresses Discovered to Be Up-regulated in Cultured Glioma Cells Compared With Normal Brain Tissue
1.
Pahl  HL Signal transduction from the endoplasmic reticulum to the cell nucleus. Physiol Rev 1999;79683- 701
PubMed
2.
Fathallah-Shaykh  HHe  BZhao  L-JBadruddin  A A mathematical algorithm for discovering states of expression from direct genetic comparison by microarrays. Nucleic Acids Res 2004;323807- 3814
PubMedArticle
3.
Fathallah-Shaykh  HMHe  BZhao  L-J  et al.  Genomic expression discovery predicts pathways and opposing functions behind phenotypes. J Biol Chem 2003;27823830- 23833
PubMedArticle
4.
Fathallah-Shaykh  HRigen  MZhao  L-J  et al.  Mathematical modeling of noise and discovery of genetic expression classes in gliomas. Oncogene 2002;217164- 7174
PubMedArticle
5.
Filomeni  GAquilano  KRotilio  GCiriolo  MR Reactive oxygen species-dependent c-Jun NH2-terminal kinase/c-Jun signaling cascade mediates neuroblastoma cell death induced by diallyl disulfide. Cancer Res 2003;635940- 5949
PubMed
6.
Petrosillo  GRuggiero  FMParadies  G Role of reactive oxygen species and cardiolipin in the release of cytochrome c from mitochondria. FASEB J 2003;172202- 2208
PubMedArticle
7.
Sanli  GBlaber  M Structural assembly of the active site in an aldo-keto reductase by NADPH cofactor. J Mol Biol 2001;3091209- 1218
PubMedArticle
8.
Srivastava  SChandra  ABhatnagar  ASrivastava  SKAnsari  NH Lipid peroxidation product, 4-hydroxynonenal and its conjugate with GSH are excellent substrates of bovine lens aldose reductase. Biochem Biophys Res Commun 1995;217741- 746
PubMedArticle
9.
Shih  AYJohnson  DAWong  G  et al.  Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J Neurosci 2003;233394- 3406
PubMed
10.
Sekhar  KRCrooks  PASonar  VN  et al.  NADPH oxidase activity is essential for Keap1/Nrf2-mediated induction of GCLC in response to 2-indol-3-yl- methylenequinuclidin-3-ols. Cancer Res 2003;635636- 5645
PubMed
11.
Lee  JMCalkins  MJChan  KKan  YWJohnson  JA Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis. J Biol Chem 2003;27812029- 12038
PubMedArticle
12.
Nonn  LBerggren  MPowis  G Increased expression of mitochondrial peroxiredoxin-3 (thioredoxin peroxidase-2) protects cancer cells against hypoxia and drug-induced hydrogen peroxide-dependent apoptosis. Mol Cancer Res 2003;1682- 689
PubMed
13.
Berggren  MIHusbeck  BSamulitis  BBaker  AFGallegos  APowis  G Thioredoxin peroxidase-1 (peroxiredoxin-1) is increased in thioredoxin-1 transfected cells and results in enhanced protection against apoptosis caused by hydrogen peroxide but not by other agents including dexamethasone, etoposide, and doxorubicin. Arch Biochem Biophys 2001;392103- 109
PubMedArticle
14.
Dinkova-Kostova  ATHoltzclaw  WDCole  RN  et al.  Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci U S A 2002;9911908- 11913
PubMedArticle
15.
McMahon  MItoh  KYamamoto  MHayes  JD Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression. J Biol Chem 2003;27821592- 21600
PubMedArticle
16.
Zipper  LMMulcahy  RT The Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm. J Biol Chem 2002;27736544- 36552
PubMedArticle
17.
Wakabayashi  NItoh  KWakabayashi  J  et al.  Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat Genet 2003;35238- 245
PubMedArticle
18.
Velichkova  MHasson  T Keap1 in adhesion complexes. Cell Motil Cytoskeleton 2003;56109- 119
PubMedArticle
19.
Schreck  RRieber  PBaeuerle  PA Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J 1991;102247- 2258
PubMed
20.
Wang  HWang  HZhang  WHuang  HJLiao  WSFuller  GN Analysis of activation status of Akt, NFkappaB, and Stat3 in human diffuse gliomas. Lab Invest 2004;84941- 951
PubMedArticle
21.
Robe  PABentires-Alj  MBonif  M  et al.  In vitro and in vivo activity of the nuclear factor-kappaB inhibitor sulfasalazine in human glioblastomas. Clin Cancer Res 2004;105595- 5603
PubMedArticle
22.
Bharti  ACAggarwal  BB Nuclear factor-kappa B and cancer: its role in prevention and therapy. Biochem Pharmacol 2002;64883- 888
PubMedArticle
23.
Yamaji  RFujita  KTakahashi  S  et al.  Hypoxia up-regulates glyceraldehyde-3-phosphate dehydrogenase in mouse brain capillary endothelial cells: involvement of Na+/Ca2+ exchanger. Biochim Biophys Acta 2003;1593269- 276
PubMedArticle
24.
Kim  JHLee  SPark  JB  et al.  Hydrogen peroxide induces association between glyceraldehyde 3-phosphate dehydrogenase and phospholipase D2 to facilitate phospholipase D2 activation in PC12 cells. J Neurochem 2003;851228- 1236
PubMedArticle
25.
Zuzak  TJSteinhoff  DFSutton  LNPhillips  PCEggert  AGrotzer  MA Loss of caspase-8 mRNA expression is common in childhood primitive neuroectodermal brain tumour/medulloblastoma. Eur J Cancer 2002;3883- 91
PubMedArticle
26.
van der Vlies  DPap  EHPost  JACelis  JEWirtz  KW Endoplasmic reticulum resident proteins of normal human dermal fibroblasts are the major targets for oxidative stress induced by hydrogen peroxide. Biochem J 2002;366825- 830
PubMed
27.
Derkx  PMMadrid  SM The foldase CYPB is a component of the secretory pathway of Aspergillus niger and contains the endoplasmic reticulum retention signal HEEL. Mol Genet Genomics 2001;266537- 545
PubMedArticle
28.
Pilon  MSchekman  RRomisch  K Sec61p mediates export of a misfolded secretory protein from the endoplasmic reticulum to the cytosol for degradation. EMBO J 1997;164540- 4548
PubMedArticle
29.
Ma  YHendershot  LM Delineation of the negative feedback regulatory loop that controls protein translation during ER stress. J Biol Chem 2003;27834864- 34873
PubMedArticle
30.
Brush  MHWeiser  DCShenolikar  S Growth arrest and DNA damage-inducible protein GADD34 targets protein phosphatase 1 alpha to the endoplasmic reticulum and promotes dephosphorylation of the alpha subunit of eukaryotic translation initiation factor 2. Mol Cell Biol 2003;231292- 1303
PubMedArticle
31.
Connor  JHWeiser  DCLi  SHallenbeck  JMShenolikar  S Growth arrest and DNA damage-inducible protein GADD34 assembles a novel signaling complex containing protein phosphatase 1 and inhibitor. Mol Cell Biol 2001;216841- 6850
PubMedArticle
32.
Novoa  IZeng  HHarding  HPRon  D Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol 2001;1531011- 1022
PubMedArticle
33.
He  CHGong  PHu  B  et al.  Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein: implication for heme oxygenase-1 gene regulation. J Biol Chem 2001;27620858- 20865
PubMedArticle
34.
Rutkowski  DTKaufman  RJ All roads lead to ATF4. Dev Cell 2003;4442- 444
PubMedArticle
35.
Ichijo  HNishida  EIrie  K  et al.  Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 1997;27590- 94
PubMedArticle
36.
Tobiume  KMatsuzawa  ATakahashi  T  et al.  ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO Rep 2001;2222- 228
PubMedArticle
37.
Hatai  TMatsuzawa  AInoshita  S  et al.  Execution of apoptosis signal-regulating kinase 1 (ASK1)-induced apoptosis by the mitochondria-dependent caspase activation. J Biol Chem 2000;27526576- 26581
PubMedArticle
38.
Takeda  KMatsuzawa  ANishitoh  HIchijo  H Roles of MAPKKK ASK1 in stress-induced cell death. Cell Struct Funct 2003;2823- 29
PubMedArticle
39.
Urano  FWang  XBertolotti  A  et al.  Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 2000;287664- 666
PubMedArticle
40.
Kaneko  MNiinuma  YNomura  Y Activation signal of nuclear factor-kappaB in response to endoplasmic reticulum stress is transduced via IRE1 and tumor necrosis factor receptor-associated factor 2. Biol Pharm Bull 2003;26931- 935
PubMedArticle
41.
Chen  XShen  JPrywes  R The luminal domain of ATF6 senses endoplasmic reticulum (ER) stress and causes translocation of ATF6 from the ER to the Golgi. J Biol Chem 2002;27713045- 13052
PubMedArticle
42.
Ye  JRawson  RBKomuro  R  et al.  ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell 2000;61355- 1364
PubMedArticle
43.
Wang  YShen  JArenzana  NTirasophon  WKaufman  RJPrywes  R Activation of ATF6 and an ATF6 DNA binding site by the endoplasmic reticulum stress response. J Biol Chem 2000;27527013- 27020
PubMed
44.
Berridge  MJ The endoplasmic reticulum: a multifunctional signaling organelle. Cell Calcium 2002;32235- 249
PubMedArticle
45.
Lincoln  DTAli Emadi  EMTonissen  KFClarke  FM The thioredoxin-thioredoxin reductase system: over-expression in human cancer. Anticancer Res 2003;232425- 2433
PubMed
46.
Perquin  MOster  TMaul  AFroment  NUntereiner  MBagrel  D The glutathione-related detoxification system is increased in human breast cancer in correlation with clinical and histopathological features. J Cancer Res Clin Oncol 2001;127368- 374
PubMedArticle
47.
Banerjee  DMadhusoodanan  UKNayak  SJacob  J Urinary hydrogen peroxide: a probable marker of oxidative stress in malignancy. Clin Chim Acta 2003;334205- 209
PubMedArticle
48.
Senthil  KAranganathan  SNalini  N Evidence of oxidative stress in the circulation of ovarian cancer patients. Clin Chim Acta 2004;33927- 32
PubMedArticle
49.
Fathallah-Shaykh  H Darts in the dark cure animal but not human brain tumors. Arch Neurol 2002;59721- 724
PubMedArticle
Original Contribution
February 2005

Genomic Discovery Reveals a Molecular System for Resistance to Oxidative and Endoplasmic Reticulum Stress in Cultured Glioma

Author Affiliations

Author Affiliation: Department of Neurological Sciences, Section of Neuro-Oncology, Rush University Medical Center, Chicago, Ill.

Arch Neurol. 2005;62(2):233-236. doi:10.1001/archneur.62.2.233
Abstract

Oxygen is required for respiration and the energetic processes that enable aerobic life. Reactive oxygen species and free radicals, by-products of oxygen use, cause DNA damage and induce endoplasmic reticulum (ER) stress and apoptosis. However, rapidly multiplying cancer cells are resistant to ER and oxidative stress–induced apoptosis. The present article reports the results of highly specific genome-scale expression discovery used to identify genes differentially expressed in cultured glioma cells vs normal brain tissue. The discovered states of expression reveal a cohesive molecular system that protects rapidly growing glioma cells from ER and oxidative stress–induced apoptosis.

Oxidative and endoplasmic reticulum (ER) stress are physiologic mechanisms that prevent aberrant growth by the activation of programmed cell death. A cost associated with oxygen use is the formation of reactive oxygen species (ROS) that activate oxidative and ER stress responses, which lead to apoptosis. However, cancer cells can survive both high oxygen demand and misfolded proteins and still maintain rapid growth.

The ER is one of the largest cell organelles: its membrane constitutes more than half of the total membrane present in the cell, and its lumen makes up more than 10% of the cell volume. The ER has 2 essential functions: (1) folding, glycosylating, and sorting proteins to their proper destination and (2) synthesizing of lipids and cholesterol of the cell membranes. A quality-control mechanism ensures that only correctly folded proteins exit the ER. Incorrectly folded proteins are retained and ultimately degraded. Disruption of ER homeostasis interferes with protein folding and leads to the accumulation of unfolded and misfolded proteins in the ER lumen. This condition has been designated ER stress. Endoplasmic reticulum stress may arise from any of the following: (1) accumulation of unfolded or misfolded proteins, (2) starvation of glucose (important for glycosylation), (3) oxidative stress, and (4) starvation of cholesterol. Activation of the ER stress response leads to protein synthesis inhibition and apoptosis.1

Recent reports have described a mathematical algorithm for highly specific discovery (MASH) from the genome-scale expression profiling of 2 samples.2,3 In the present report, MASH is applied to analyze the expression data sets of 19 200 complementary DNAs in cultured glioma cells as compared with normal brain tissue, which appears to best represent genetic expression in normal adult glial cells. Embryonal human glial cultures are not readily available, and genetic expression differs between embryonal and mature cells. The discovered states of genetic expression reveal a cohesive system of molecular interactions that protect glioma cells from ROS and ER-induced apoptosis.

METHODS
GLIOMA CELL LINES

The present experiments profile RNA isolated from 6 glioma cell lines and from normal brain tissue. Two glioma cell lines were purchased from American Type Culture Collection, Manassas, Va (T98G and U373MG). The others were cultured from a glioblastoma, an oligodendroglioma, and 2 astrocytoma tumor samples (provided by Herbert Engelhard, MD, PhD, University of Illinois at Chicago).

MICROARRAYS

Normal brain RNA was obtained by pooling RNA from human occipital lobes harvested from 4 individuals with no known neurologic disease whose brains were frozen less than 3 hours after death. Tumor RNA samples were extracted from 6 cultured glioma cell lines. The quality of RNA was assayed by gel electrophoresis; only high-quality RNA was processed. Tumor RNA was profiled in comparison with aliquots from the same normal brain RNA. Microarray experiments used 19K microarrays (Ontario Cancer Institute, Ontario, Canada); the design included probe switching (dye swapping), as previously described.3,4 Each 19K microarray contained 19 200 complementary DNAs spotted in duplicates. The experiments generated 4 replicate measurements per gene and tumor.

DATA ANALYSIS

We applied MASH to analyze the data sets2 and discovered the states of genetic expression, up- or down-regulation. The false discovery rate for MASH in 19K microarrays is 1 in 192 000 measurements. We followed the following steps in the listed order: (1) applied MASH to find the genes differentially expressed in each cell line compared with the normal brain sample; (2) found the set of genes, S, that were extracted by MASH in at least 1 of the 6 cell lines; and (3) identified the 4 “raw” replicate ratios of each of the genes of S in each cell line. We then applied a filter consisting of the following “fuzzy logic” rules in sequence: (1) all 4 replicate log 2 (ratios) of a gene in any cell line to be of the same sign and different than 0 (all 4 show either up- or down-regulation); (2) the mean of the 4 replicate ratios to be either greater than 1.5 or less than 0.67; (3) if rules 1 and 2 both apply, compute the mean of the replicate log 2 expression values; otherwise, exclude the genes by transforming the log 2 expression to 0; (4) exclude genes that are not resistant to both rules 1 and 2 in at least 5 of 6 cell lines; and (5) exclude genes that are simultaneously up-regulated in one cell line and down-regulated in another.3

RESULTS

The data revealed that 268 genes were consistently up- or down-regulated in at least 5 of 6 cultured glioma cell lines compared with normal brain tissue. The Table shows 21 up-regulated genes related to ER and oxidative stress.

OXIDATIVE STRESS

High ROS activity initiates a cascade of events that culminate in commitment to apoptosis through activation of the mitochondrial pathway and release of cytochrome c.5,6 The expression data (Table and Figure) reveal that gliomas adapted to high ROS activity by activating several pathways that protect them against apoptosis.

AKR1A1 and AKR1C1 are up-regulated in glioma cells; they belong to the aldo-keto reductase superfamily of enzymes, which bind to the nicotinamide adenine dinucleotide (NAD+) as cofactors.7 Oxidative stress is associated with degradation of lipid peroxides, which generates toxic lipid aldehydes. AKR1A1 and AKR1C1 protect cells by efficiently detoxifying and reducing aldehydes and ketones.8

Several antioxidant genes are up-regulated in glioma cells. These include PDG, TALDO1, AFG3L1, and ANT2 and the phase 2 genes NQO1, GSTP1, GCLM, PRDX1, and TXNRD1.911 The antioxidant proteins protect against ROS-induced apoptosis by preventing the release of cytochrome c.12,13 Reactive oxygen species induce the expression of phase 2 genes by disrupting the cytoplasmic complex between the actin-binding protein Keap-1 (Kelchlike ECH-associated protein 1) and the transcription factor Nrf2 (NF erythroid 2–related factor 2), thereby releasing Nrf2 to migrate to the nucleus where it activates the antioxidant response element.1418

MCP1 and GAPD are up-regulated in gliomas. Nuclear factor κB (NF-κB) is directly activated by application of oxidizing agents, particularly hydrogen peroxide.19 Several laboratories have reported constitutive activation of NF-κB in cultured glioma cells and glioblastoma surgical samples.20,21 Activated NF-κB induces MCP1 and protects against apoptosis by regulating several antiapoptotic proteins including BCL2 (B-cell lymphoma/leukemia 2).22GAPD is transcriptionally up-regulated by hypoxia23 ; it mediates hydrogen peroxide–dependent activation of phospholipase D2, which protects against apoptosis.24

ER STRESS RESPONSE

Glioma cells appear to acquire pathways to (1) recover from ER stress–induced protein inhibition and (2) prevent apoptosis. Chaperones within the ER lumen are responsible for folding newly synthesized proteins into their tertiary structures prior to their export to the Golgi. KDELR1, CYPB, and Sec61A1 are up-regulated in gliomas. The receptor of ER proteins that share the carboxy-terminal sequence Lys-Asp-Glu-Leu (KDEL) contributes to a quality control system where newly synthesized misfolded or partially assembled proteins are retrieved to the ER.25 The ER molecular chaperone CYPB is susceptible to oxidation by ROS.26,27Sec61A1 is a subunit of the Sec61p channel that mediates the retrograde export of a misfolded secretory protein from the endoplasmic reticulum to the cytosol for degradation.28

The ER stress response initiates several signaling pathways, including the phosphorylation of PERK (double-stranded RNA-dependent protein kinase–like ER kinase or pancreatic ER kinase) and the oligomerization and autophosphorylation of IRE1 (inositol requiring kinase 1) on the ER membrane leading to the formation of the IRE1-TRAF2 (tumor necrosis factor receptor–associated factor 2) complex (Figure). ATF4 is up-regulated in glioma cells. The oligomerization and autophosphorylation of PERK sets off a phosphorylation cascade leading to inactivation of the alpha subunit of eukaryotic initiation factor 2 (eIF-2α) resulting in switching off protein synthesis. ATF4 opposes ER stress-induced protein inhibition by inducing GADD34 (growth arrest and DNA damage–inducible protein), which dephosphorylates eIF-2α causing protein synthesis recovery.29 GADD34 recruits type 1 protein serine/threonine α to the ER where it dephosphorylates eIF-2α.2932 ATF4 also interacts with Nrf2 to regulate the expression of the genes induced by the antioxidant response element.33,34

PP5 is up-regulated in glioma cells. The up-regulation of PP5C appears to grant glioma cells a survival advantage by neutralizing the proapoptotic effects of apoptosis signal-regulating kinase 1 (ASK1). Ubiquitously expressed, ASK1 is a MAPKKK (mitogen-activated protein kinase kinase kinase) that binds to IRE1 and TRAF2 to generate the IRE1-TRAF2-ASK1 complex, which activates the JNK (c-Jun N-terminal protein kinase) and p38 pathways and induces apoptosis through mitochondria-dependent caspase activation.3539 PP5 is a binding partner of ASK1; it directly dephosphorylates ASK1 and thereby inactivates its activity both in vitro and in vivo.

Paradoxically, the IRE1-TRAF2 complex may also protect against apoptosis by activating NF-κB.1,40 Both S1P and GRP94 are up-regulated in glioma cells. IRE1 activation appears to be upstream of ATF6 in the ER stress-signaling pathway.25 ATF6 contains a single transmembrane domain with 272 amino acids oriented in the lumen of the ER, which senses ER stress and causes translocation to the Golgi, where it is cut in its luminal domain by S1P.41,42 S1P-mediated cleavage releases ATF6 from cell membranes for translocation to the nucleus, where it binds to DNA and induces the expression of several glucose-regulated proteins including tumor rejection antigen (gp96) 1. The latter stabilizes calcium homeostasis in the ER and protects against oxidative stress–mediated death.43,44

COMMENT

These results reveal a molecular system in cultured glioma cells that protects against oxidative and ER stress–induced apoptosis. The rapid multiplication rate of cancer cells generates high levels of ROS, but a cohesive system of several molecular pathways protects rapidly growing glioma cells from ROS and ER stress–mediated apoptosis (Figure). Lincoln et al45 and Perquin et al46 find that antioxidant genes are up-regulated in aggressive thyroid, prostate, colorectal, and breast carcinomas. Furthermore, patients with cancer show changes in their plasma and urine consistent with excessive oxidative stress.47 For example, patients with ovarian cancer have elevated plasma levels of thiobarbituric acid–reactive substances and conjugated dienes and low levels of antioxidants such as superoxide dismutase, catalase, vitamin C, and vitamin E.48

The survival of patients with malignant astrocytomas is now about the same as it was 30 years ago.49 The resistance of gliomas may stem from the redundancy and multiplicity of their molecular systems (Figure). The data present additional support to the idea that biological phenotypes are created by complex systems of gene-to-gene and gene-to-protein molecular interactions.3 Perturbation experiments and mathematical modeling of the dynamic behavior of this system may identify therapeutic targets that are best suited to reverse the resistant phenotype and kill glioma cells.

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Article Information

Correspondence: Hassan M. Fathallah-Shaykh, MD, Department of Neurological Sciences, Section of Neuro-Oncology, Rush University Medical Center, 1735 W Harrison St, Third Floor–Cohn Building, Chicago, IL 60612 (hfathall@rush.edu).

Accepted for Publication: July 20, 2004.

References
1.
Pahl  HL Signal transduction from the endoplasmic reticulum to the cell nucleus. Physiol Rev 1999;79683- 701
PubMed
2.
Fathallah-Shaykh  HHe  BZhao  L-JBadruddin  A A mathematical algorithm for discovering states of expression from direct genetic comparison by microarrays. Nucleic Acids Res 2004;323807- 3814
PubMedArticle
3.
Fathallah-Shaykh  HMHe  BZhao  L-J  et al.  Genomic expression discovery predicts pathways and opposing functions behind phenotypes. J Biol Chem 2003;27823830- 23833
PubMedArticle
4.
Fathallah-Shaykh  HRigen  MZhao  L-J  et al.  Mathematical modeling of noise and discovery of genetic expression classes in gliomas. Oncogene 2002;217164- 7174
PubMedArticle
5.
Filomeni  GAquilano  KRotilio  GCiriolo  MR Reactive oxygen species-dependent c-Jun NH2-terminal kinase/c-Jun signaling cascade mediates neuroblastoma cell death induced by diallyl disulfide. Cancer Res 2003;635940- 5949
PubMed
6.
Petrosillo  GRuggiero  FMParadies  G Role of reactive oxygen species and cardiolipin in the release of cytochrome c from mitochondria. FASEB J 2003;172202- 2208
PubMedArticle
7.
Sanli  GBlaber  M Structural assembly of the active site in an aldo-keto reductase by NADPH cofactor. J Mol Biol 2001;3091209- 1218
PubMedArticle
8.
Srivastava  SChandra  ABhatnagar  ASrivastava  SKAnsari  NH Lipid peroxidation product, 4-hydroxynonenal and its conjugate with GSH are excellent substrates of bovine lens aldose reductase. Biochem Biophys Res Commun 1995;217741- 746
PubMedArticle
9.
Shih  AYJohnson  DAWong  G  et al.  Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J Neurosci 2003;233394- 3406
PubMed
10.
Sekhar  KRCrooks  PASonar  VN  et al.  NADPH oxidase activity is essential for Keap1/Nrf2-mediated induction of GCLC in response to 2-indol-3-yl- methylenequinuclidin-3-ols. Cancer Res 2003;635636- 5645
PubMed
11.
Lee  JMCalkins  MJChan  KKan  YWJohnson  JA Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis. J Biol Chem 2003;27812029- 12038
PubMedArticle
12.
Nonn  LBerggren  MPowis  G Increased expression of mitochondrial peroxiredoxin-3 (thioredoxin peroxidase-2) protects cancer cells against hypoxia and drug-induced hydrogen peroxide-dependent apoptosis. Mol Cancer Res 2003;1682- 689
PubMed
13.
Berggren  MIHusbeck  BSamulitis  BBaker  AFGallegos  APowis  G Thioredoxin peroxidase-1 (peroxiredoxin-1) is increased in thioredoxin-1 transfected cells and results in enhanced protection against apoptosis caused by hydrogen peroxide but not by other agents including dexamethasone, etoposide, and doxorubicin. Arch Biochem Biophys 2001;392103- 109
PubMedArticle
14.
Dinkova-Kostova  ATHoltzclaw  WDCole  RN  et al.  Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci U S A 2002;9911908- 11913
PubMedArticle
15.
McMahon  MItoh  KYamamoto  MHayes  JD Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression. J Biol Chem 2003;27821592- 21600
PubMedArticle
16.
Zipper  LMMulcahy  RT The Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm. J Biol Chem 2002;27736544- 36552
PubMedArticle
17.
Wakabayashi  NItoh  KWakabayashi  J  et al.  Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat Genet 2003;35238- 245
PubMedArticle
18.
Velichkova  MHasson  T Keap1 in adhesion complexes. Cell Motil Cytoskeleton 2003;56109- 119
PubMedArticle
19.
Schreck  RRieber  PBaeuerle  PA Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J 1991;102247- 2258
PubMed
20.
Wang  HWang  HZhang  WHuang  HJLiao  WSFuller  GN Analysis of activation status of Akt, NFkappaB, and Stat3 in human diffuse gliomas. Lab Invest 2004;84941- 951
PubMedArticle
21.
Robe  PABentires-Alj  MBonif  M  et al.  In vitro and in vivo activity of the nuclear factor-kappaB inhibitor sulfasalazine in human glioblastomas. Clin Cancer Res 2004;105595- 5603
PubMedArticle
22.
Bharti  ACAggarwal  BB Nuclear factor-kappa B and cancer: its role in prevention and therapy. Biochem Pharmacol 2002;64883- 888
PubMedArticle
23.
Yamaji  RFujita  KTakahashi  S  et al.  Hypoxia up-regulates glyceraldehyde-3-phosphate dehydrogenase in mouse brain capillary endothelial cells: involvement of Na+/Ca2+ exchanger. Biochim Biophys Acta 2003;1593269- 276
PubMedArticle
24.
Kim  JHLee  SPark  JB  et al.  Hydrogen peroxide induces association between glyceraldehyde 3-phosphate dehydrogenase and phospholipase D2 to facilitate phospholipase D2 activation in PC12 cells. J Neurochem 2003;851228- 1236
PubMedArticle
25.
Zuzak  TJSteinhoff  DFSutton  LNPhillips  PCEggert  AGrotzer  MA Loss of caspase-8 mRNA expression is common in childhood primitive neuroectodermal brain tumour/medulloblastoma. Eur J Cancer 2002;3883- 91
PubMedArticle
26.
van der Vlies  DPap  EHPost  JACelis  JEWirtz  KW Endoplasmic reticulum resident proteins of normal human dermal fibroblasts are the major targets for oxidative stress induced by hydrogen peroxide. Biochem J 2002;366825- 830
PubMed
27.
Derkx  PMMadrid  SM The foldase CYPB is a component of the secretory pathway of Aspergillus niger and contains the endoplasmic reticulum retention signal HEEL. Mol Genet Genomics 2001;266537- 545
PubMedArticle
28.
Pilon  MSchekman  RRomisch  K Sec61p mediates export of a misfolded secretory protein from the endoplasmic reticulum to the cytosol for degradation. EMBO J 1997;164540- 4548
PubMedArticle
29.
Ma  YHendershot  LM Delineation of the negative feedback regulatory loop that controls protein translation during ER stress. J Biol Chem 2003;27834864- 34873
PubMedArticle
30.
Brush  MHWeiser  DCShenolikar  S Growth arrest and DNA damage-inducible protein GADD34 targets protein phosphatase 1 alpha to the endoplasmic reticulum and promotes dephosphorylation of the alpha subunit of eukaryotic translation initiation factor 2. Mol Cell Biol 2003;231292- 1303
PubMedArticle
31.
Connor  JHWeiser  DCLi  SHallenbeck  JMShenolikar  S Growth arrest and DNA damage-inducible protein GADD34 assembles a novel signaling complex containing protein phosphatase 1 and inhibitor. Mol Cell Biol 2001;216841- 6850
PubMedArticle
32.
Novoa  IZeng  HHarding  HPRon  D Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol 2001;1531011- 1022
PubMedArticle
33.
He  CHGong  PHu  B  et al.  Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein: implication for heme oxygenase-1 gene regulation. J Biol Chem 2001;27620858- 20865
PubMedArticle
34.
Rutkowski  DTKaufman  RJ All roads lead to ATF4. Dev Cell 2003;4442- 444
PubMedArticle
35.
Ichijo  HNishida  EIrie  K  et al.  Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 1997;27590- 94
PubMedArticle
36.
Tobiume  KMatsuzawa  ATakahashi  T  et al.  ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO Rep 2001;2222- 228
PubMedArticle
37.
Hatai  TMatsuzawa  AInoshita  S  et al.  Execution of apoptosis signal-regulating kinase 1 (ASK1)-induced apoptosis by the mitochondria-dependent caspase activation. J Biol Chem 2000;27526576- 26581
PubMedArticle
38.
Takeda  KMatsuzawa  ANishitoh  HIchijo  H Roles of MAPKKK ASK1 in stress-induced cell death. Cell Struct Funct 2003;2823- 29
PubMedArticle
39.
Urano  FWang  XBertolotti  A  et al.  Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 2000;287664- 666
PubMedArticle
40.
Kaneko  MNiinuma  YNomura  Y Activation signal of nuclear factor-kappaB in response to endoplasmic reticulum stress is transduced via IRE1 and tumor necrosis factor receptor-associated factor 2. Biol Pharm Bull 2003;26931- 935
PubMedArticle
41.
Chen  XShen  JPrywes  R The luminal domain of ATF6 senses endoplasmic reticulum (ER) stress and causes translocation of ATF6 from the ER to the Golgi. J Biol Chem 2002;27713045- 13052
PubMedArticle
42.
Ye  JRawson  RBKomuro  R  et al.  ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell 2000;61355- 1364
PubMedArticle
43.
Wang  YShen  JArenzana  NTirasophon  WKaufman  RJPrywes  R Activation of ATF6 and an ATF6 DNA binding site by the endoplasmic reticulum stress response. J Biol Chem 2000;27527013- 27020
PubMed
44.
Berridge  MJ The endoplasmic reticulum: a multifunctional signaling organelle. Cell Calcium 2002;32235- 249
PubMedArticle
45.
Lincoln  DTAli Emadi  EMTonissen  KFClarke  FM The thioredoxin-thioredoxin reductase system: over-expression in human cancer. Anticancer Res 2003;232425- 2433
PubMed
46.
Perquin  MOster  TMaul  AFroment  NUntereiner  MBagrel  D The glutathione-related detoxification system is increased in human breast cancer in correlation with clinical and histopathological features. J Cancer Res Clin Oncol 2001;127368- 374
PubMedArticle
47.
Banerjee  DMadhusoodanan  UKNayak  SJacob  J Urinary hydrogen peroxide: a probable marker of oxidative stress in malignancy. Clin Chim Acta 2003;334205- 209
PubMedArticle
48.
Senthil  KAranganathan  SNalini  N Evidence of oxidative stress in the circulation of ovarian cancer patients. Clin Chim Acta 2004;33927- 32
PubMedArticle
49.
Fathallah-Shaykh  H Darts in the dark cure animal but not human brain tumors. Arch Neurol 2002;59721- 724
PubMedArticle
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