* Department of Pathobiology, and Department of Microbiology, University of Tennessee, Knoxville, Tennessee 37996, and
Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, South Korea
1 To whom correspondence should be addressed at Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996. Fax: (865) 974-5616. E-mail: sbaek2{at}utk.edu.
Received December 6, 2004; accepted February 9, 2005
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ABSTRACT |
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Key Words: PAHs; PPAR; PPAR
; EGR-1; GSK-3ß.
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INTRODUCTION |
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Many chronic diseases, including cancer and cardiovascular diseases have been linked to heredity and/or the environment, which can either enhance or inhibit the disease process. One such molecular link between disease and the environment is early growth response-1 (EGR-1, also known as NGFI-A, Zif268, Krox24, and Tis8). EGR-1 is the prototypical member of a family of zinc finger transcription factors that includes at least three other members, EGR-2, -3, and -4. EGR-1 is especially induced by a range of physiological and environmental stimuli including growth factors, cytokines, ultraviolet light, ionizing radiation, and mechanical injury (Gashler and Sukhatme, 1995; Khachigian and Collins, 1998
). EGR-1 appears to be critically involved in several diseases including angiogenesis and tumor formation. Alteration in expression could contribute to the deleterious effects of PAH exposure. Recently, Martinez et al. reported that halogenated aromatic hydrocarbon, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induces EGR-1 expression in human lung carcinoma cells (Martinez et al., 2004
). However, expression of EGR-1 in nonneoplastic cells underlies diverse pathophysiological responses such as survival responses to damaging irradiation (Huang et al., 1999
), development of vascular occlusion in arteriosclerosis (Silverman and Collins, 1999
), and formation of severe pulmonary emphysema (Zhang et al., 2000
). In addition to these diverse actions, expression of EGR-1 is commonly down-regulated in tumor cells in contrast with their normal tissue counterparts (Calogero et al., 2004
; Hao et al., 2002
; Huang et al., 1997
; Levin et al., 1995
; Shozu et al., 2004
). However, EGR-1 is expressed at a higher level and promotes cell growth in prostate cancer when compared with normal tissues (Eid et al., 1998
; Thigpen et al., 1996
). Thus, EGR-1 has multiple functions in tumorigenesis, and the exact biological function of EGR-1 may be dependent on cell context as well as tissue types (Baek et al., 2004
). Nonetheless, the EGR-1's role in vascular disease has been firmly established by the fact that EGR-1 controls the expression of several genes implicated in the pathogenesis of atherosclerosis and restenosis (Breslow, 1996
; Harja et al., 2004
; McCaffrey et al., 2000
; Silverman and Collins, 1999
).
Peroxisome proliferator activated receptors (PPARs) are another molecular link between chronic disease and the environment. PPARs are members of the nuclear receptor superfamily and exist as three subtypes designated , ß (or
), and
. Among those, PPAR
activation is responsible for the pleiotropic effects of peroxisome proliferator such as enzyme induction, peroxisome proliferation, liver enlargement, and tumors (Klaunig et al., 2003
). PPAR
also plays a critical role in regulation of cellular uptake and ß-oxidation of fatty acids (Berger and Moller, 2002
; Marx et al., 2004
). In contrast, PPAR
(also known as PPARß) is widely expressed with relatively higher levels in brain, colon, and skin. Although there have been extensive studies on PPAR
, much less is known about the function of PPAR
. Nonetheless, recent studies suggest that PPAR
plays a role in colon cancer (Gupta et al., 2004
; He et al., 1999
; Wang et al., 2004
), and preadipocyte proliferation (Hansen et al., 2001
).
We hypothesized that transcription factors, EGR-1 and PPARs may link environmental toxic compounds to human diseases. The aim of this study is to determine whether PAHs affect EGR-1 and PPARs activity and to identify the different activity of PAHs in reporter system. In this study, fifteen PAHs, which are commonly found in the environment, were examined as potential activators of PPAR or PPARß/
, and inducer of EGR-1 gene expression in A549 human lung adenocarcinoma cells and HCT-116 human colorectal adeno carcinoma cells. The luciferase reporter genes were used to measure the activity of PPARs and transactivation of the EGR-1 promoter. We have demonstrated that some PAHs may activate PPAR
and PPARß/
, and transactivate EGR-1 promoter activity. Among those, benz(a)anthracene (BaA) induces EGR-1 and PPAR activation in culture systems. Furthermore feral mice (Peramyscus gossypinus) trapped along the floodplain of a Superfund site with high levels of PAH contamination demonstrated significant up-regulation of EGR-1 and down-regulation of GSK-3ß, a PPAR target gene. These data provide evidence for diverse effects of PAHs that may be important in diseases linked to environmental pollution such as cardiovascular disease and carcinogenesis.
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MATERIALS AND METHODS |
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Plasmids.
EGR-1 promoter (1260 to +35) linked to the luciferase gene (pEGR1260-Luc) was described previously (Baek et al., 2003). The plasmids used for studying PPAR
and PPARß/
activators were a reporter gene containing four copies of a Gal4 binding site (MH100x4-TK-Luc) and chimeric receptors (pCMX-Gal-mPPAR
-LBD for PPAR
and pCMX-Gal-mPPAR
-LBD for PPAR
). In this system, when a compound binds to the ligand binding domain (LBD) from PPAR
or PPAR
of the chimeric receptor (pCMX-Gal4-mPPAR
-LBD or pCMX-Gal-mPPAR
-LBD), then the DNA binding domain of the yeast Gal4 (denoted as Gal) binds to co-transfected Gal4 binding site and initiates transcription of the firefly luciferase (Luc). A reporter plasmid containing three copies of the PPAR response element (PPREx3-TK-Luc) and a mouse PPAR
cDNA (pCDNA3-mPPAR
) were previously described (Nixon et al., 2003
). This system directly measures activation of PPAR
via transcriptional activation of the luciferase reporter gene as a result of PPAR
binding to the PPAR response element (PPRE). All the PPAR and PPAR reporter plasmids were generously provided by Dr. Ronald M. Evans (Howard Hughes Medical Institute, CA).
Transient transfections and luciferase reporter assays.
Cells (1 x 105 cells/well) were cultured in twelve-well plates in culture medium containing 10% FBS. After growth for 16 h, the internal control, 0.05 µg pRL-null (Promega, WI) and 0.5 µg of the other plasmids were transfected using LipofectAMINE (Life Technologies, Inc.) according to the manufacturer's protocol. After 24 h, the media were changed and the cells were treated with the various PAHs dissolved in DMSO. The final concentration of DMSO did not exceed 0.1% (v/v) in any of the samples. Treatments with PAHs were performed under serum-free conditions. After 24 h treatment, the cells were washed with PBS and harvested in 1X luciferase lysis buffer. The luciferase activity was measured by a dual luciferase assay kit (Promega, WI), and normalized to the internal control, pRL-null (renilla luciferase) activity.
Animal studies.
Feral mice (Peramyscus gossypinus) were trapped along the floodplain of the Chattanooga Superfund site and in a control site two miles upstream from the contaminated section of creek. All animal procedures were in compliance with the National Institute of Health guidelines on animal use and were approved by the University of Tennessee Institutional Animal Care and Use Committee. Traps were set each evening and checked each morning. Trapped animals were transported to the laboratory and anesthetized with CO2. After the chest cavities were opened, the mice were exsanguinated by cardiac puncture and the distal aorta, heart and lungs perfused with phosphate buffered saline (PBS) to remove clotted blood. Sections of heart, lung, and colon were removed and snap-frozen in liquid nitrogen for Western blot analysis.
Western blot analysis.
The level of protein expression was evaluated by Western blot analysis. FaO cells were grown to 6080% confluency in 6 cm plates, followed by 24 h treatment of selected PAHs in the absence of serum. Total cell lysates were isolated using RIPA buffer (1x phosphate-buffered saline, 1% Nonidet P-40, 0.5% sodium deoxycholate, and 0.1% SDS) containing proteinase inhibitor, and the soluble protein concentrations were determined by BCA protein assay kit (Pierce, Rockford, IL). For feral mouse tissues, frozen samples were lysed in ice-cold RIPA buffer as described above. All lysate proteins were separated by SDS-PAGE and transferred for 1 h onto nitrocellulose membrane (Osmonics Inc., MN). The blots were blocked for 1 h with 5% skim milk in Tris-buffered saline and Tween 0.05% and probed with GSK-3ß (Cell Signaling, MA), EGR-1 (Santa Cruz Biotech., CA), CYP4A (Affinity Bioreagent, Golden, CO), or Actin (Santa Cruz Biotech., CA) antibody at 4°C overnight. After washing with Tris-buffered saline and Tween 0.05%, the blots were treated with horseradish peroxidase-conjugated secondary antibody for 1 h and washed several times. The signals were detected by the enhanced chemiluminescence system (Amersham Biosciences, Arlington Height, IL). The signal intensities were measured by NIH Image program (Scion Corp., MD).
Statistical analysis.
For luciferase activities of transient transfection experiments, data were expressed as mean ± SD for at least three independent repeats. For quantitative analyses, analysis of variance (ANOVA) with Tukey's multiple comparison test or t-test was used to compare mean values. SAS for Windows (9.1) (SAS Institute Inc., Cary, NC) statistical analysis software was used. A p-value of less than 0.05 was considered significant.
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RESULTS |
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DISCUSSION |
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EGR-1 can induce expression of a set of vasculature genes, such as PDGF-A and B chain, bFGF, TGF-ß, TNF-, and intracellular adhesion molecule-1. Expression of the EGR-1 is elevated in prostate cancer and correlates with tumor progression. Thus, EGR-1 is the key mediator in orchestrating the functional characteristics of the vessel wall and tumorigenesis. However, EGR-1 can be related to anti-tumorigenesis and pro-tumorigenesis, depending on cell and tissue types. While EGR-1 induces anti-tumorigenic proteins including p53, PTEN, and NAG-1 (Baek et al., 2005
), EGR-1 is expressed at a higher level and promotes cell growth in prostate cancer (Eid et al., 1998
; Thigpen et al., 1996
). Thus, EGR-1 could play a role in both cell proliferation and growth arrest. In contrast to EGR-1 functions in tumorigenesis, experimental evidence is emerging to link EGR-1 to chronic vascular and inflammatory stress in vivo. The role of EGR-1 in atherosclerosis related to PAH exposure has not been examined. In this study, EGR-1 was not up-regulated in heart tissue from mice exposed naturally to environmental contaminants; however, vascular tissue was not examined. Further studies are warranted to evaluate the potential role of EGR-1 in atherosclerosis progression related to atherosclerosis and heart disease.
PPAR is a key contributor in the processes of peroxisome proliferation, hypertrophy, cell proliferation, and hepatocarcinogenesis in vivo. Its over-expression is observed in advanced prostate cancer (Collett et al., 2000
), and activation of PPAR
promotes cell proliferation in breast cancer cells (Klaunig et al., 2003
; Suchanek et al., 2002
). In addition, activation of PPAR
has been demonstrated to modulate many aspects of lipoprotein metabolism and inflammation in vitro, as well as in animal and human studies (Israelian-Konaraki and Reaven, 2004
). Thus, activation of PPAR
may play a role in disease such as tumorigenesis and atherogenesis. On the other hand, the activation of PPARß/
plays an anti-apoptotic role in keratinocytes via transcriptional control of the AKT signaling pathway (Di-Poi et al., 2002
). Genetic disruption of PPARß/
also decreases the tumorigenicity of human colon cancer cells transplanted into mice (Park et al., 2001
). Our results support the contention that some PAHs with known carcinogenic activity are relatively strong PPAR
and PPARß/
activators as assessed by reporter system. These results support that some PAHs may induce chronic disease through PPAR activation mechanism other than AhR activation. These results also suggest that minute differences in PAH structure result in the activation of two different PPARs.
In this report, we have shown that GSK-3ß is suppressed in heart tissue from mice trapped in a highly contaminated Superfund site as well as in the FaO cells. GSK-3ß is known to be a negative regulator of cardiac hypertrophy (Hardt and Sadoshima, 2002), and we have recently reported that AKT/GSK-3ß plays an important role in apoptosis (Yamaguchi et al., 2004
). Therefore, the suppression of GSK-3ß by environmental contaminants such as PAHs may be important in the processes by which environmental pollution accelerates cardiac disorders or tumorigenesis such as cardiomyopathy or cancer; however, further studies may be required to elucidate the exact molecular mechanism.
In conclusion, our data suggest that some PAHs, particulary BaA, are able to activate EGR-1 promoter and act as an activator of PPAR and PPARß/
in vitro. BaA can activate target genes of PPAR
and PPARß/
, thereby repressing the GSK-3ß expression in vitro and in vivo and inducing the CYP4A expression in vitro. The repression of GSK-3ß and activation of EGR-1 by some PAHs may provide a novel approach to elucidating the various effects of PAHs on human chronic disease.
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ACKNOWLEDGMENTS |
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