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[Cancer Research 63, 7689-7693, November 15, 2003]
© 2003 American Association for Cancer Research

Regular Articles

Inhibitor of Nuclear Factor {kappa}B Kinase Deficiency Enhances Oxidative Stress and Prolongs c-Jun NH2-Terminal Kinase Activation Induced by Arsenic

Fei Chen1, Vince Castranova1, Zhiwei Li2, Michael Karin2 and Xianglin Shi1

1 Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia,
2 Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 
Stress signals activate both inhibitor of nuclear factor-{kappa}B kinase (IKKß) and c-Jun NH2-terminal kinase (JNK). It was shown recently that IKK-dependent nuclear factor {kappa}B activation results in attenuation of tumor necrosis factor {alpha}-induced JNK activation. How that negative cross-talk between nuclear factor {kappa}B and JNK occurs is not well-understood. By using wild-type and Ikkß gene knockout (Ikkß-/-) mouse embryo fibroblasts, we found that IKKß deficiency results in prolongation of arsenic-induced JNK activation, which was not due to the decreased expression of GADD45ß or X-linked Inhibitor of Apoptosis (XIAP), as suggested previously for RelA-/- cells treated with tumor necrosis factor {alpha}. This enhanced JNK activation was largely associated with an oxidative stress response as indicated by elevated expression of heme oxygenase-1 and the accumulation of H2O2 in Ikkß-/- cells. Expression profiling experiments revealed an increased expression of p450 family CYP1B1 mRNA in Ikkß-/- cells compared with wild-type cells. Inhibition of CYP1B1 reduced both oxidative stress and arsenic-stimulated JNK activation. Thus, increased CYP1B1 expression is central to and seems to be responsible for sensitizing Ikkß-/- cells to stress-induced JNK activation.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 
Transcription factor NF{kappa}B3 plays central roles in the cellular response to a variety of stress signals by regulating numerous genes (1, 2, 3) . Signals from various stimuli induce activation of upstream kinases, mainly the IKK complex that contains two catalytic kinase subunits, IKK{alpha} and IKKß, and a structural and regulatory component named NEMO/IKK{gamma}. Activated IKK phosphorylates inhibitor of NF{kappa}B {alpha} and inhibitor of NF{kappa}B ß, leading to their ubiquitination and degradation, and subsequent NF{kappa}B activation and nuclear translocation.

The JNK acts as an integration point for multiple intracellular biochemical signals governing a wide variety of cellular processes such as proliferation, differentiation, apoptosis, migration, transcriptional regulation, and development (4) . JNK targets specific transcription factors and, thus, mediates immediate-early gene expression in response to various stress signals including UV radiation, oxidative stress, protein malfolding, osmotical shock, and inflammatory mediators. These transcription factors include activator protein 1, ATF-2, Elk-1, and p53. A number of extracellular or intracellular signaling molecules, such as cytokines or mitogen-activated protein kinase kinase kinases, that activate IKK-NF{kappa}B signaling pathways can also contribute to the activation of JNK (5) . Thus, cross-talk between NF{kappa}B and JNK occurs under many circumstances. We have shown previously that inhibition of IKKß and NF{kappa}B activities via expression of catalytically inactive IKKß in epithelial cells enhances stress-induced JNK activation caused by As3+ treatment (6) . In the present study, we additionally demonstrated that the enhanced JNK activation in As3+-treated IKKß-deficient cells is partially due to oxidative stress resulting from the increased expression of cyp1B1, a p450 gene family member.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS AND DISCUSSION
 REFERENCES
 
Cell Culture and Western Blotting.
MEFs were cultured as described previously (7) . Whole cell extracts were prepared using SDS-PAGE sample buffer and subjected to SDS-PAGE in 8 or 10% gels. The resolved proteins were transferred to a nitrocellulose membrane. Western blotting was performed using antibodies as indicated in figures or figure legends.

H2O2 Assay by DCFDA Staining and Confocal Microscopy.
MEFs cultured on glass coverslips in six-well tissue culture plates were stained with 5 µM CM-H2-DCFDA (Molecular Probes, Inc., Eugene, OR) in dark for 30 min. After extensive washing with PBS buffer and fixation with 10% formaldehyde for 10 min at room temperature in dark, the coverslips were mounted on slides. The H2O2 generation was detected as a result of the oxidation of DCFDA (excitation, 488 nm; emission, 515–540 nm) by confocal microscopy. A single rapid scan was performed for each slide with identical parameters of contrast and brightness. The cell images were randomly selected from the digital interference contrast channel for each sample.

Gene Profiling and RT-PCR.
Total RNA was isolated from MEFs and subjected to gene profiling using Affymetrix mouse GeneChip following the manufacturer’s instructions. To verify the gene profiling data, some of the differentially expressed genes in WT and Ikkß-/- MEFs were analyzed by RT-PCR.


   RESULTS AND DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
REFERENCES
 
To understand the mechanisms by which IKKß inhibition potentiates JNK activation, we used MEFs derived from WT and Ikkß gene knockout (Ikkß-/-) mice (7) . Expression of IKK subunits in these cells was determined by immunoblotting after treatment with As3+, a classic stress inducer (8 , 9) , for various time periods. A relatively higher concentration of As3+, 50 µM, rather than the lower concentrations relevant to the chronic environmental exposure, was used in this study for the purpose of short experimentation. As expected, whereas equal levels of IKK{alpha} were noted between WT and Ikkß-/- cells, expression of IKKß was limited to WT cells (Fig. 1)Citation . Both types of cells exhibited activation of JNK in response to As3+, as described previously (10) . However, JNK activation detected by immunoblotting with an antibody against Thr183/Tyr185-phosphorylated JNK protein occurred with different kinetics in the two cell types. In WT cells, JNK activation was elevated rapidly by As3+, peaking ~4 h after stimulation, and declined by 24 h. In Ikkß-/- cells, however, JNK activation was sustained and peaked at 24 h after stimulation (Fig. 1A)Citation . Similarly, an enhanced activation of p38 and Erk, two additional members of mitogen-activated protein kinase family, was noted in Ikkß-/- cells. However, the enhancement of p38 and Erk in Ikkß-/- cells was much weaker than that of JNK. Fig. 1BCitation shows a normalized value of four detailed time course experiments for JNK activation. In WT cells, the decline of JNK activation by As3+ started at 8 h. The activation of JNK, however, was still near maximum at 32 h of As3+ treatment in Ikkß-/- cells (also see Supplementary Fig. 1).



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  		Fig. 1. Prolonged JNK activation in Ikkß-/- cells. A, WT and Ikkß-/- cells were cultured in six-well tissue culture plates in medium containing 5% FBS for 2 days followed by culture in medium containing 0.1% FBS for 1 day. Cells were then treated with 50 µM As3+ for different time periods as indicated. Total cellular protein was extracted and subjected to immunoblot analysis using antibodies against IKK{alpha}, IKKß, phospho- or non-phospho-JNK, phospho- or non-phospho-p38, and phospho- or non-phospho-Erk as indicated. Lanes 1 and 6 indicate that cells cultured for 24 h without As3+ treatment. B, a more detailed time course study for As3+-induced JNK activation in both WT cells and Ikkß-/- cells. JNK activation was normalized by determining the density ratios of phospho-JNK bands versus non-phospho-JNK bands using TotalLab software. * indicated significant difference of JNK activation induced by As3+ between WT and Ikkß-/- cells at the same time point (**, P <= 0.005; * P <= 0.05).

 
The prolonged activation of JNK in Ikkß-/- cells may indicate enhanced activity of upstream kinases that activate JNK. MEKK1 is a Mr 196,000 mammalian serine/threonine kinase that may be responsible for stress-induced JNK activation. After stress signals, MEKK1 is cleaved by proteases into an active COOH-terminal Mr 91,000 kinase fragment (11) . To determine the status of proteolytic activation of MEKK1, an immunoblot was performed using an antibody that recognizes both a full-length and an active COOH-terminal kinase fragment of MEKK1. As depicted in Fig. 2ACitation , Ikkß-/- cells showed basal cleavage of MEKK1 that was not seen in WT cells. In addition, Ikkß-/- cells exhibit higher basal levels of activated caspase-3, a cysteine protease that cleaves MEKK1 (Ref. 11 ; Fig. 2BCitation ), as evidenced by the appearance of the activated Mr 12,000 caspase-3 fragment. However, there was no correlation between late-phase JNK activation by As3+ and MEKK1 cleavage or caspase-3 activation, which were most apparent in Ikkß-/- cells in the absence of As3+ (compare Fig. 1Citation with Fig. 2, A and BCitation ).



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  		Fig. 2. Spontaneous cleavage of MEKK1 and enhanced caspase-3 activation in Ikkß-/- cells. Cells were cultured as described in Fig. 1Citation . Total cellular protein was used for immunoblot using antibodies against MEKK1 (A) and caspase-3 (B), respectively. Results are representation of three experiments. Lanes 1 and 6 in each figure indicate that cells cultured for 24 h without As3+ treatment. C, Expression of MKPs in WT and Ikkß-/- cells. Total cellular proteins were prepared from WT or Ikkß-/- cells cultured in the absence or presence of 50 µM As3+. Immunoblotting was performed by sequential hybridization of the same membrane with antibodies against MKP1, MKP2, MKP3, PAC1, and Actin.

 
It should be noted that previous studies have shown that JNK activation by As3+ is largely dependent on inhibition of MKPs, which normally dephosphorylate and inhibit the activity of JNK (10) . To investigate whether potentiated JNK activation in Ikkß-/- cells is due to deficiency or reduced expression of MKPs, the protein levels of several MKPs in both WT cells and Ikkß-/- cells were determined. As indicated in Fig. 2CCitation , immunoblot analysis revealed an increase rather than a decrease in MKP1 and MKP2 expression or induction in Ikkß-/- cells (Fig. 2C)Citation . PAC1, another dual-specific MKP, was expressed equally in WT and Ikkß-/- cells, whereas the expression of MKP3 could be detected only in Ikkß-/- cells. Both cells did not express a relatively specific JNK phosphatase M3/6 as indicated by RT-PCR analysis (data not shown). Therefore, it is less likely that decreased expression of MKPs is responsible for the prolonged JNK activation by As3+ in Ikkß-/- cells.

There are a number of other factors that contribute to the activation of JNK signaling, among which oxidative stress is most prominent (12 , 13) . Furthermore, the MKPs responsible for JNK inhibition are cysteine-dependent enzymes, of which the activity require the presence of reduced cysteine and are, therefore, sensitive to oxidative stress (10) . To ascertain whether the enhanced JNK activation by As3+ in Ikkß-/- cells was the result of redox imbalance, we first measured the expression of HO-1, a sensitive and reliable indicator of oxidative stress (14) . To visualize the basal expression of HO-1 in both WT and Ikkß-/- cells, we overexposed the immunoblot membrane. Whereas HO-1 was nearly undetectable under basal conditions in WT cells, a notable HO-1 band was present in nonstimulated Ikkß-/- cells (Fig. 3ACitation , top panel). As3+ treatment caused a much stronger induction of HO-1 in Ikkß-/- cells than that in WT cells (Fig. 3A)Citation . To investigate whether oxidative stress was responsible for the increased basal and As3+-induced HO-1 expression in Ikkß-/- cells, we examined H2O2 accumulation in both WT and Ikkß-/- MEFs using DCFDA, of which the fluorescence is proportional to the level of intracellular H2O2. Confocal microscopy analysis indicated that only a marginal increase of H2O2 could be detected in the WT cells upon treatment with 50 µM of As3+ for 12 h (Fig. 3B)Citation . In contrast, significant levels of H2O2 were present in Ikkß-/- cells even before treatment with As3+ (Fig. 3B)Citation . Treatment with As3+ resulted in an additional increase its H2O2 production in these cells, possibly because of partial depletion of intracellular reduced glutathione pool as suggested (15) , although the change of reduced glutathione did not reach statistical significance (Supplementary Fig. 2Citation ). To exclude the possible nonspecific detection of H2O2 by DCFDA, the increased H2O2 generation in Ikkß-/- cells was additionally confirmed biochemically using OXIS Bioxytech H2O2 detection kit (data not shown).



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  		Fig. 3. IKKß deficiency causes oxidative stress. A, WT and Ikkß-/- cells treated with or without 50 µM As3+ for 0, 4, or 24 h. The cell lysates were used for an immunoblot of HO-1 (top panel) or ß-actin (bottom panel). Results are representative of three experiments. Lanes 1 and 6 indicate that cells cultured for 24 h without As3+ treatment. B, both WT and Ikkß-/- cells were cultured in six-well tissue culture plates (105/well) containing glass slides in 5% FBS for 2 days and then in 0.1% FBS for 1 day. The cells were additionally cultured in 0.1% FBS containing 50 µM As3+ for 12 h. H2O2 accumulation was determined by incubation of the cells with DCFDA for 30 min followed by confocal microscopic analysis.

 
ROS are generated from molecular oxygen either by mitochondrial electron transport chains or by cytosolic metabolic reactions. Spontaneous or enhanced oxidative stress may reflect either overproduction of ROS or accumulation of ROS resulting from dysfunction of endogenous antioxidant enzymes. A number of enzymes with peroxidase activity, such as cytochromes p450 family members, cyclooxygenases or lipoxygenases, are responsible for generation of ROS in the cytosol (16 , 17) . Whereas expression profiling experiments by DNA microarray analysis revealed no decrease in mRNA expression of several major antioxidant enzymes in Ikkß-/- cells, a 2.8-fold increase in the mRNA level of p450 protein CYP1B1 was noted (Table 1)Citation . To verify the DNA microarray data, we performed RT-PCR analyses using total RNA derived from both WT and Ikkß-/- cells (Fig. 4A)Citation . A roughly equal expression of GADD45ß, GADD45{gamma}, and GAPDH mRNAs was observed between WT and Ikkß-/- cells. In agreement with the DNA microarray results, a substantial increase in CYP1B1 mRNA and a marginal increase of SOD1 mRNA were detected in Ikkß-/- cells. In addition, an appreciable decrease of metallothionein II, a major metal binding protein that may act as a scavenger of hydroxyl radicals (18 , 19) , was observed in Ikkß-/- cells.


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  		Table 1 Relative levels of gene expression in Ikkß-/- MEF versus WT MEF

 


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  		Fig. 4. Increased expression of CYP1B1 mRNA in Ikkß-/- cells is responsible for the enhanced JNK activation. A, RT-PCR was performed using total RNAs extracted from both WT and Ikkß-/- cells for the detection of mRNA expression by using primer sets for GADD45ß, GADD45{gamma}, SOD1, CYP1B1, Metallothionein II, and GAPDH. Results are representative of two experiments. B, inhibition of CYP1B1 activity reduces oxidative stress in Ikkß-/- cells. The Ikkß-/- cells were preincubated with 5 or 10 mM NAC, 31 or 62 µM SKF525A, or 25, 50, 100, and 200 µM {alpha}-naphthoflavone for 2 h. The cells were then treated with 50 µM As3+ for 24 h and subjected to the immunoblot for HO-1 or actin. The bars indicate average of two experiments, which determined the density ratios of HO-1 bands versus actin bands using TotalLab software. C, inhibition of CYP1B1 activity reduces JNK activation in Ikkß-/- cells. The same immunoblot membrane of (B) was stripped and reprobed with antibodies against phospho-JNK or non-phospho-JNK. The bars indicate average of two experiments, which determined the density ratios of phospho-JNK bands versus non-phospho-JNK bands using TotalLab software.

 
It is well known that p450 family members catalyze a large spectrum of oxidation of endobiotics and xenobiotic chemicals, resulting ROS generation (20) . To determine whether increased CYP1B1 expression in Ikkß-/- cells might be responsible for the observed changes in H2O2 production and JNK activation, we pretreated the cells with NAC and p450 inhibitors. NAC, as has been shown previously (10) , inhibited the induction of HO-1 and JNK activation in Ikkß-/-cells treated with As3+ for 16 h (Fig. 4, B and CCitation , Lanes 3 and 4). SKF525A, an inhibitor for CYP1A1, 2A, and 4A (21 , 22) , showed no effect on either HO-1 induction or JNK activation (Fig. 4, B and CCitation , Lanes 5 and 6). In contrast, the CYP1B1 inhibitor, {alpha}-naphthoflavone, inhibited HO-1 induction and JNK activation in a dose-dependent manner in Ikkß-/- cells treated with 50 µM As3+ (Fig. 4, B and CCitation , Lanes 7–10). In WT cells, although both NAC and {alpha}-naphthoflavone were able to inhibit JNK activation induced by As3+ treatment for 4 h, neither NAC nor {alpha}-naphthoflavone showed a significant effect on JNK activation in WT cells treated with As3+ for 16 h, possibly because of the fact that As3+-induced JNK activation at this time point had already declined to an undetectable level (Supplementary Fig. 3Citation ).

There are several possibilities that explain the increased expression of CYP1B1, and the resulting oxidative stress and prolonged JNK activation in Ikkß-/- cells. Deficiency in IKKß reduced the basal activity of NF{kappa}B (data not shown), a transcription factor that antagonizes the AhR (23 , 24) , a nuclear protein required for the transcription of CYP1B1 gene that contains a number of AhR binding sites (XRE; Ref. 25 ). In addition, impairment of NF{kappa}B signaling possibly decreases expression of the AhR repressor gene, leading to the enhancement of AhR function and increased expression of CYP1B1.

Increased JNK activation in RelA-/- MEF treated with tumor necrosis factor {alpha} has been attributed previously to the decreased expression of GADD45ß and XIAP (26 , 27) . Intriguingly, both GADD45ß and XIAP have also been shown to be capable of activating JNK through affecting upstream kinase (28 , 29) . In the present study, no substantial difference of basal GADD45ß mRNA was observed in WT cells and Ikkß-/- cells (Table 1Citation ; Fig. 4ACitation ). In addition, no difference in the levels of XIAP expression between WT and Ikkß-/- MEF was detected (data not shown). Therefore, it is unlikely that decreased GADD45ß or XIAP expression contributed to an enhanced As3+-induced JNK activation in Ikkß-/- cells. Instead, we believe that oxidative stress partially resulted from the increased expression of CYP1B1 in Ikkß-/- cells is responsible for the sustained As3+-induced JNK activation. Although oxidative stress itself is not very potent in basal JNK activation, it is synergistic for stress-induced JNK activation, possibly through inactivation of MKPs or endogenous JNK signaling inhibitors, such as glutathione S-transferase {pi} and thioredoxin (30 , 31) .


   ACKNOWLEDGMENTS
 
We thank Dr. Lyndell Millecchia in National Institute for Occupational Safety and Health for assistance in confocal microscopy.

Note Added in Proof

During the reviewing period of this manuscript, Sakon et al. reported, in the August 1st issue of EMBO J (22:5530), that increased ROS accumulation is responsible for the prolonged TNFa-induced JNK activation in rela-/- cells.


   FOOTNOTES
 
Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Fei Chen, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, PPRB, 1095 Willowdale Road, Morgantown, WV 26505. E-mail: lfd3{at}cdc.gov

3 The abbreviations used are: NF{kappa}B, nuclear factor {kappa}B; IKK, inhibitor of nuclear factor {kappa}B kinase; JNK, c-Jun NH2-terminal kinase; As3+, arsenic; MEF, mouse embryo fibroblast; DCFDA, 2',7'-dichlorofluorescein diacetate; RT-PCR, reverse transcription-PCR; WT, wild-type; MEKK, mitogen-activated protein kinase kinase kinase; MKP, mitogen-activated protein kinase phosphatase; HO-1, heme oxygenase-1; ROS, reactive oxygen species; NAC, N-acetyl-L-cysteine; AhR, aryl hydrocarbon receptor; FBS, fetal bovine serum. Back

Received 7/ 2/03. Revised 8/ 6/03. Accepted 8/11/03.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 

  1. Karin M., Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-{kappa}B activity. Annu. Rev. Immunol., 18: 621-663, 2000.[Medline]
  2. Ghosh S., Karin M. Missing pieces in the NF-{kappa}B puzzle. Cell, 109 (Suppl.): S81-S96, 2002.
  3. Baldwin A. S., Jr. Series introduction: the transcription factor NF-{kappa}B and human disease. J. Clin. Investig., 107: 3-6, 2001.[Medline]
  4. Davis R. J. Signal transduction by the JNK group of MAP kinases. Cell, 103: 239-252, 2000.[Medline]
  5. Chen G., Goeddel D. V. TNF-R1 signaling: a beautiful pathway. Science (Wash. DC), 296: 1634-1635, 2002.[Abstract/Free Full Text]
  6. Chen F., Lu Y., Zhang Z., Vallyathan V., Ding M., Castranova V., Shi X. Opposite effect of NF-{kappa}B and c-Jun N-terminal kinase on p53-independent GADD45 induction by arsenite. J. Biol. Chem., 276: 11414-11419, 2001.[Abstract/Free Full Text]
  7. Li Z. W., Chu W., Hu Y., Delhase M., Deerinck T., Ellisman M., Johnson R., Karin M. The IKKß subunit of I{kappa}B kinase (IKK) is essential for nuclear factor {kappa}B activation and prevention of apoptosis. J. Exp. Med., 189: 1839-1845, 1999.[Abstract/Free Full Text]
  8. Centeno J. A., Mullick F. G., Martinez L., Page N. P., Gibb H., Longfellow D., Thompson C., Ladich E. R. Pathology related to chronic arsenic exposure. Environ. Health Perspect., 110 (Suppl. 5): 883-886, 2002.
  9. Hei T. K., Liu S. X., Waldren C. Mutagenicity of arsenic in mammalian cells: role of reactive oxygen species. Proc. Natl. Acad. Sci. USA, 95: 8103-8107, 1998.[Abstract/Free Full Text]
  10. Cavigelli M., Li W. W., Lin A., Su B., Yoshioka K., Karin M. The tumor promoter arsenite stimulates AP-1 activity by inhibiting a JNK phosphatase. EMBO J., 15: 6269-6279, 1996.[Medline]
  11. Widmann C., Gerwins P., Johnson N. L., Jarpe M. B., Johnson G. L. MEK kinase 1, a substrate for DEVD-directed caspases, is involved in genotoxin-induced apoptosis. Mol. Cell Biol., 18: 2416-2429, 1998.[Abstract/Free Full Text]
  12. Benhar M., Dalyot I., Engelberg D., Levitzki A. Enhanced ROS production in oncogenically transformed cells potentiates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase activation and sensitization to genotoxic stress. Mol. Cell Biol., 21: 6913-6926, 2001.[Abstract/Free Full Text]
  13. Chen Y. R., Shrivastava A., Tan T. H. Down-regulation of the c-Jun N-terminal kinase (JNK) phosphatase M3/6 and activation of JNK by hydrogen peroxide and pyrrolidine dithiocarbamate. Oncogene, 20: 367-374, 2001.[Medline]
  14. Vile G. F., Basu-Modak S., Waltner C., Tyrrell R. M. Heme oxygenase 1 mediates an adaptive response to oxidative stress in human skin fibroblasts. Proc. Natl. Acad. Sci. USA, 91: 2607-2610, 1994.[Abstract/Free Full Text]
  15. Shimizu M., Hochadel J. F., Fulmer B. A., Waalkes M. P. Effect of glutathione depletion and metallothionein gene expression on arsenic-induced cytotoxicity and c-myc expression in vitro. Toxicol. Sci., 45: 204-211, 1998.[Abstract/Free Full Text]
  16. Keller H., Dreyer C., Medin J., Mahfoudi A., Ozato K., Wahli W. Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers. Proc. Natl. Acad. Sci. USA, 90: 2160-2164, 1993.[Abstract/Free Full Text]
  17. Poulos T. L., Raag R. Cytochrome P450cam: crystallography, oxygen activation, and electron transfer. FASEB J., 6: 674-679, 1992.[Abstract]
  18. Dalton T. P., Shertzer H. G., Puga A. Regulation of gene expression by reactive oxygen. Annu. Rev. Pharmacol. Toxicol., 39: 67-101, 1999.[Medline]
  19. Thornalley P. J., Vasak M. Possible role for metallothionein in protection against radiation-induced oxidative stress. Kinetics and mechanism of its reaction with superoxide and hydroxyl radicals. Biochim. Biophys. Acta, 827: 36-44, 1985.[Medline]
  20. Guengerich F. P. Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem. Res. Toxicol., 14: 611-650, 2001.[Medline]
  21. Sun J., Sui X., Bradbury J. A., Zeldin D. C., Conte M. S., Liao J. K. Inhibition of vascular smooth muscle cell migration by cytochrome p450 epoxygenase-derived eicosanoids. Circ. Res., 90: 1020-1027, 2002.[Abstract/Free Full Text]
  22. Bednar M. M., Gross C. E., Balazy M. K., Belosludtsev Y., Colella D. T., Falck J. R., Balazy M. 16(R)-hydroxy-5, 8, 11, 14-eicosatetraenoic acid, a new arachidonate metabolite in human polymorphonuclear leukocytes. Biochem. Pharmacol., 60: 447-455, 2000.[Medline]
  23. Tian Y., Ke S., Denison M. S., Rabson A. B., Gallo M. A. Ah receptor and NF-{kappa}B interactions, a potential mechanism for dioxin toxicity. J. Biol. Chem., 274: 510-515, 1999.[Abstract/Free Full Text]
  24. Morgan E. T. Regulation of cytochrome p450 by inflammatory mediators: why and how?. Drug Metab. Dispos., 29: 207-212, 2001.[Abstract/Free Full Text]
  25. Zhang L., Savas U., Alexander D. L., Jefcoate C. R. Characterization of the mouse Cyp1B1 gene. Identification of an enhancer region that directs aryl hydrocarbon receptor-mediated constitutive and induced expression. J. Biol. Chem., 273: 5174-5183, 1998.[Abstract/Free Full Text]
  26. De Smaele E., Zazzeroni F., Papa S., Nguyen D. U., Jin R., Jones J., Cong R., Franzoso G. Induction of gadd45ß by NF-{kappa}B downregulates pro-apoptotic JNK signalling. Nature (Lond.), 414: 308-313, 2001.[Medline]
  27. Tang G., Minemoto Y., Dibling B., Purcell N. H., Li Z., Karin M., Lin A. Inhibition of JNK activation through NF-{kappa}B target genes. Nature (Lond.), 414: 313-317, 2001.[Medline]
  28. Takekawa M., Saito H. A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Cell, 95: 521-530, 1998.[Medline]
  29. Suzuki Y., Nakabayashi Y., Takahashi R. Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death. Proc. Natl. Acad. Sci. USA, 98: 8662-8667, 2001.[Abstract/Free Full Text]
  30. Adler V., Yin Z., Fuchs S. Y., Benezra M., Rosario L., Tew K. D., Pincus M. R., Sardana M., Henderson C. J., Wolf C. R., Davis R. J., Ronai Z. Regulation of JNK signaling by GSTp. EMBO J., 18: 1321-1334, 1999.[Medline]
  31. Liu H., Nishitoh H., Ichijo H., Kyriakis J. M. Activation of apoptosis signal-regulating kinase 1 (ASK1) by tumor necrosis factor receptor-associated factor 2 requires prior dissociation of the ASK1 inhibitor thioredoxin. Mol. Cell Biol., 20: 2198-2208, 2000.[Abstract/Free Full Text]



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FASEB J, August 1, 2006; 20(10): 1589 - 1598.
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 Nucleic Acids ResHome page
Y. Zhang, D. Bhatia, H. Xia, V. Castranova, X. Shi, and F. Chen
Nucleolin links to arsenic-induced stabilization of GADD45{alpha} mRNA
Nucleic Acids Res., January 18, 2006; 34(2): 485 - 495.
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 Mol. Cell. Biol.Home page
Y. Dai, M. Rahmani, P. Dent, and S. Grant
Blockade of Histone Deacetylase Inhibitor-Induced RelA/p65 Acetylation and NF-{kappa}B Activation Potentiates Apoptosis in Leukemia Cells through a Process Mediated by Oxidative Damage, XIAP Downregulation, and c-Jun N-Terminal Kinase 1 Activation
Mol. Cell. Biol., July 1, 2005; 25(13): 5429 - 5444.
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 Cancer Res.Home page
Y. Zhang and F. Chen
Reactive Oxygen Species (ROS), Troublemakers between Nuclear Factor-{kappa}B (NF-{kappa}B) and c-Jun NH2-terminal Kinase (JNK)
Cancer Res., March 15, 2004; 64(6): 1902 - 1905.
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