Progress in Cell Cycle Research, Vol. 5, 261-267, (2003) (Meijer, L., Jézéquel, A., and Roberge, M., eds.) chapter 26
Aryl hydrocarbon receptor-mediated cell cycle control
Cornelis J. Elferink
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor responsive to both natural and man-made environmental compounds. AhR-mediated changes in gene expression frequently affect cell growth, and recent evidence reveals a direct role for the AhR in cell cycle control. This review examines the functional interaction between the AhR and the retinoblastoma tumor suppressor protein (pRb), and its impact on the G1 phase of the cell cycle. The discussion emphasizes gaps in our mechanistic understanding, and reveals the AhR signaling pathway as a novel drug target to control cell proliferation. THE ARYL HYDROCARBON RECEPTOR The environment harbors an enormous number of both natural and man-made substances with genotoxic properties. The polycyclic aromatic hydrocarbons (PAHs) comprise a family of compounds that modify DNA with bulky lesions and, because of their prevalence in the environment, pose a significant human health hazard. Benzo[a]pyrene (BaP) represents a well characterized member of the PAHs. BaP is generated during combustion of many organic substances such as coal, cigarettes and gasoline, and is a classical complete carcinogen (1). BaP requires biotransformation by the CYP1A1 gene product, cytochrome P450IA1, to the active carcinogenic form, benzo[a]pyrene-7,8-diol9,10-epoxide (BPDE). BPDE can covalently attach to DNA to form a variety of adducts. DNA repair to remove these adducts triggers cell cycle arrest in cycling cells concomitant with increased p53 protein expression, consistent with the protective role p53 plays following DNA damage (2). BaP carcinogenicity is lost however, in aryl hydrocarbon receptor (AhR) knockout mice (3). Since the AhR is a ligand-activated transcription factor that induces CYP1A1 gene expression in response to BaP binding, the evidence indicates that biotransformation of BaP to the genotoxic BPDE depends on CYP1A1 expression. This biotransformation paradigm resulting in carcinogenesis represents a well-established mechanism whereby the AhR can indirectly influence cell proliferation. Certain nongenotoxic tumor-promoting chemicals found in the environment are also AhR agonists, and reveal a more direct role for the AhR in cell cycle control. These include the dioxins and polychlorinated biphenyls (PCBs). An environmental pollutant that is a prototypical AhR agonist is 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD), possessing a dissociation constant for the receptor in the picomolar range (4). Despite concerted efforts, a physiologically relevant endogenous ligand for the AhR remains to be identified. These efforts are hampered in part due to the unprecedented promiscuity exhibited by the AhR, capable of binding a structurally diverse array of exogenous ligands. The biological ramifications of this diversity amongst ligands is dramatically illustrated by the observation that PAH but not TCDD, is cytotoxic to mouse oocytes 261 due to ligand-specific AhR-mediated expression of the pro-apoptotic Bax gene (5). The differential response between PAH and TCDD is conveyed by a single base pair flanking the AhR DNA-binding site upstream of the Bax gene promoter, suggesting that ligand binding translates into conformational differences that affect DNA sequence selectivity by the AhR. The AhR belongs to the PAS subfamily of basic helixloop-helix family of transcriptional regulators (6). Members of the PAS family include HIF-1α involved in oxygen sensing and angiogenesis (7), the circadian rhythm proteins CLOCK and BMAL1, (8) and the AhR nuclear translocator (Arnt) (9). The AhR is noteworthy for being the only member conditionally activated by a ligand. The unliganded AhR is a cytosolic protein in a complex with heat-shock protein 90 (10), the co-chaperone protein p23 (11) and the immunophilin-like AIP/ARA9/XAP2 protein (12-14). Upon ligand binding, the AhR translocates into the nucleus whereupon it heterodimerizes with the Arnt protein and binds to AhR DNA recognition sites, known as a xenobiotic response elements (XRE), upstream of target genes (Figure 1). Our understanding of AhR-regulated gene expression comes predominantly from studies of several genes coding for the drug-metabolizing enzymes CYP1A1, 1A2, 1B1 and glutathione S-transferase Ya (4, 15). AHR AS A CELL CYCLE REGULATOR The first indications A number of reports in recent years point to a role for the AhR in cell cycle control, although the precise mechanism remains ill-defined (16-22). Studies using an AhR-defective variant of the mouse hepatoma Hepa 1c1c7 cell line revealed a prolonged doubling time compared with its wild-type counterpart (17). This was attributed to protracted transit through the G1 phase, suggesting that AhR action facilitated G1 cell cycle progression. Mouse embryonic fibroblasts (MEF) from AhR null mice also grow more slowly, but this is attributed to an accumulation of cells in the G2/M phase due to altered expression of the G2/M kinases Cdk1 and Plk (22). Using AhR-null MEF cells, the AhR was shown to contribute to p300-mediated induction of DNA synthesis (S-phase progression) by the adenovirus E1A protein (23). Collectively, these observations
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Figure 1. The AhR signaling pathway. The unliganded AhR resides in the cytosol as a complex with hsp90, p23 and AIP/ARA9/XAP2 (labeled as AIP in the figure). Exogenous ligands or the presumed endogenous ligand bind the AhR, triggering receptor translocation into the nucleus where it dissociates from the cytosolic complex, forming instead a heterodimer with the Arnt protein. The AhR/Arnt dimer binds to XREs upstream of numerous target genes such as CYP1A1 to increase expression of the encoded gene products. The role of cofactors in modulating AhR-mediated gene expression represents an area of active research.
suggest that in the absence of an exogenous ligand, the AhR promotes progression through the cell cycle. In contrast, evidence dating back as far as 1984 showed that TCDD can inhibit cell proliferation (24). Confluent mouse epithelial cell cultures exhibited a diminished capacity for DNA replication in the presence of as little as 10 pM TCDD. TCDD also inhibited DNA synthesis in rat primary hepatocytes (25) and in rat liver following partial hepatectomy (26). The evidence suggests that the AhR functions to promote cell cycle progression in the absence of an exogenous ligand, whilst exposure to TCDD leads to cell cycle arrest. These seemingly contradictory observations also emerge when comparing the growth of 5L rat hepatoma cells (AhRpositive) and BP8 cells (AhR-negative cells derived from the 5L line following selection for resistance to BaP genotoxicity) (16). In the absence of TCDD, 5L cells proliferate more quickly than BP8 cells, but once exposed to TCDD the 5L cell doubling time mirrors that of BP8 cells (Figure 2). The BP8 cells however, are completely refractory to the TCDD effect on cell proliferation. Pharmacological evidence indicates that TCDD induces a G1-phase arrest that is AhR-mediated (Figure 3). The TCDD dose response reveals an ED50 of approximately 200 pM, close to the Kd of TCDD for the AhR. In addition, the highly selective AhR antagonist 3'-methoxy-4'nitroflavone (3Me4NF) completely abolished the G1 arrest response (27). Furthermore, ectopic AhR expression in the BP8 cells restores the arrest response detected in 5L cells (16, 21), confirming the receptor's participation in cell cycle control. The TCDD-induced G1 arrest in 5L cells is attributed in large part to increased expression of the cyclin-dependent kinase 2 (CDK2) inhibitor p27Kip1 (18). In keeping with the dependence on CDK2 activity for cells to enter S phase, p27Kip1 action stalls the cell cycle in G1 phase (28, 29). A key target for CDK2 activity is the retinoblastoma tumor suppressor protein, pRb (28-30). pRb is a major 262
cell cycle checkpoint control protein that is functionally inactivated by CDK-mediated phosphorylation of multiple serine and threonine residues (30). pRb has been observed to bind to a large number of molecules including both stimulatory and repressive transcription factors, kinases and phosphatases. Recent estimates are around 50 different proteins (31), although this number is likely to grow. Among the cellular partners for pRb, its regulation of E2F offers the clearest picture of how pRb controls the cell cycle (32). E2F is a family of transcription factors (E2F1-6) that bind DNA as heterodimers with the DP transcription factors (DP1-3). E2F transcriptional activity is required to express genes important for entry into S phase and DNA replication. A primary role for pRb is to restrict E2F transcriptional activity in G1 phase cells. For a comprehensive discussion on the role of pRb, E2F, CDKs and their inhibitors, the reader is directed to excellent reviews (28-32) and other chapters in this volume. The AhR-pRb interaction Recent reports from independent laboratories demonstrated that the AhR interacts with pRb through two distinct AhR domains (19-21). Speculation initially centered on a cyclin D-like LXCXE motif within the Ah receptor PAS domain (19), which site-directed mutagenesis studies subsequently confirmed as indeed conferring an AhR-pRb interaction (21). The evidence also demonstrated that maximal TCDD-induced G1 arrest and CYP1A1 induction in 5L cells relied on pRb binding with the AhR LXCXE motif (21). Reliance on pRb for maximal TCDD- inducible CYP1A1 expression implies that pRb functions as a coactivator protein, an observation that was previously reported for nuclear receptors (33, 34). Binding between AhR and pRb appears to be restricted to the hypophosphorylated "active" form of pRb (19-21). This observation is entirely consistent with other studies showing that phosphorylation of pRb at threonine-821 and threonine-826 abolishes the binding of LXCXE motif
CHAPTER 26 / AhR-MEDIATED CELL CYCLE CONTROL
Figure 2.. TCDD induces growth inhibition in rat 5L hepatoma cells. Panel A, total protein from 5L and BP8 cells was fractionated by SDS-PAGE and probed for AhR protein with an anti-AhR antibody (Western). Analysis of AhR expression was also performed by RT-PCR on total RNA from 5L and BP8 cells using primers specific for rat AhR (rAhR) and GAPDH (as a control for RT-PCR). Panel B, 5L (solid bars) and BP8 (open bars) cells (2x105) were grown in the presence of 10 nM TCDD (+) or absence of TCDD (-) for 24h or 48h and counted. The values presented are the mean ± S.D. of three independent experiments.
Figure 3. Dose response of TCDD-induced G1 phase arrest in 5L cells. Asynchronous subconfluent 5L cells were grown in the absence (Control) or presence of TCDD (10 pM-10 nM), or the presence of 1µM 3'methoxy-4'-nitroflavone (3Me4NF) ± 150 pM TCDD for 24h prior to ethanol fixation and propidium iodide staining. DNA content analyses were performed on 2x104 cells using the FACSCalibur flow cytometer equipped with CellQuest and ModFit software. The percent of cells in G1 is presented as the mean ± S.D. The dashed line denotes the G1 content in untreated (control) asynchronous cultures.
proteins to pRb (35). Given that the hypophosphorylated pRb is confined to the G0 and G1 phases of the cell cycle, the AhR-pRb interaction is likely to be cell cycle-dependent. The location of the second binding site remains less well defined but is believed to lie within an 83-amino acid region encompassing residues 589-671 in the glutaminerich region of the human AhR (19). This region lies within a complex transactivation domain (TAD) comprising the C-terminal third of the protein. A leucine residue at position 678 in the human AhR is critical for transactivation (36). Although a role for the RIP140 coactivator protein was suggested, this residue's proximity to the Q-rich region raises the interesting prospect that it may be necessary for pRb binding to the AhR. Another candidate suspected of binding to the Q-rich region is the BRG-1 protein (37). BRG-1 is a mammalian homolog of the yeast SWI/SNF2 transcriptional activator involved in chromatin remodeling to alleviate nucleosomal repression (3840). Wang and Hankinson (37) demonstrated that BRG-1 potentiates AhR transcriptional activity dependent upon an interaction between BRG-1 and the AhR Q-rich region. Interestingly, BRG-1 also binds pRb as part of a repressor complex inhibiting E2F transcriptional activation (38-40). Binding studies revealed that the BRG-1 interaction with 263
pRb occurs through an LXCXE motif (39). Hence, the possibility that BRG-1 can simultaneously bind the AhR Qrich region and pRb ought to be considered. However, a direct BRG-1-pRb interaction is unlikely to involve the BRG-1 LXCXE motif because both the pRb-AhR interaction and full receptor activity is dependent on pRb binding through the receptor's LXCXE motif (21), thus precluding a similar interaction between pRb and BRG-1. PROPOSED MECHANISMS FOR AHR-MEDIATED CELL CYCLE CONTROL A model for how TCDD induces G1 arrest (Figure 4) proposes that the AhR induces p27Kip1 protein expression thus preventing pRb phosphorylation and keeping E2F repressed. Indeed, it has been demonstrated that TCCD induces p27Kip1 in 5L cells and that the increase in p27Kip1 was responsible for the G1 arrest (18). Since hypophosphorylated pRb can function as an AhR coactivator (21), a positive feedback loop is established sustaining AhR transcriptional activity, conditional upon the continued presence of an AhR agonist. In contrast, transition through the G1/S checkpoint relies on cyclin A and E-dependent CDK2 kinase activity to phosphorylate pRb and derepress E2F-regula-
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Figure 4. A model for AhR-mediated G1 phase arrest. The diagram groups the components of the growth inhibitory and stimulatory positive feedback mechanisms discussed in the text. AhRmediated expression of p27Kip1 inhibits cell cycle progression by repressing CDK2 activity and preventing pRb hyperphosphorylation. AhR activity and signaling through this pathway depends on the continued presence of AhR agonist. E2F-regulated expression of cyclins A and E (cycA/E) increases CDK2 activity, inhibition of p27Kip1 and pRb hyperphosphorylation, resulting in S phase entry and continued cell division. The phosphorylation status of pRb influences the activity of both pathways. From Elferink, C.J., Ge, N.-L. and Levine, A. (2001) in Molecular Pharmacology 59, 664-673, with permission.
ted gene expression. In turn, E2F facilitates its own transcriptional activity by controlling expression of the cyclin A and E genes (41-45), thereby increasing CDK2 activity and hastening pRb inactivation. Thus, E2F activity also establishes a positive feedback mechanism driving entry into S phase. Collectively, the opposing actions of p27Kip1 and CDK2 function as a "binary switching mechanism" where G1/S phase transition appears to require not only the E2F transcriptional activity, but also AhR inactivation to suppress expression of p27Kip1. As a regulatory component common to each pathway, pRb hyperphosphorylation achieves both endpoints simultaneously. pRb-dependent coactivation of the AhR may also explain the observation that the viral oncoprotein E1A can suppress CYP1A1 induction (46). E1A is known to sequester pRb, suggesting that pRb may no longer be available to the AhR as a coactivator for full CYP1A1 induction. Disruption of the AhR-pRb interaction by hyperphosphorylation may also explain why oncogenic c-Ha-ras suppresses AhR activity in MCF-10A human breast cancer cells (47). Activation of c-Ha-ras and the downstream MAPK cascade in response to mitogens induces cyclin D1 expression (48), triggering an increase in cyclin D-CDK4/6 activity (28, 29). CDK4/6 not only directly phosphorylates pRb, but also sequesters p27Kip1 away from the cyclin-CDK2 complexes, thus increasing CDK2 activity and enhancing pRb phosphorylation (29). The implication is that the inhibitory effect of c-Ha-ras on AhR activity may be indirectly due to pRb hyperphosphorylation, resulting in diminished AhR transcriptional activity. Independent studies showed that the interaction between AhR and pRb actively represses E2F-dependent gene expression, as measured using an E2Fresponsive wild type dihydrofolate reductase gene promoter fused to a luciferase reporter gene (20). Ectopic expression of AhR and pRb in two human cancer cell lines, SAOS-2 and C33A that lack endogenous expression of both proteins, blocked entry of the cells into the S-phase of the cycle (20). Since pRb is selectively recruited to promoters through its interaction with E2F (32, 49) the evidence was interpreted as the AhR functioning as a transcriptional corepressor forming a quaternary complex with pRb, E2F and DP1 (the E2Fbinding partner in transactivation). Formal proof of this 264
model is currently unavailable, but may come from experiments designed to analyze protein interactions at E2Fresponsive promoters. It is worth noting that the binary switch model (Figure 4) is entirely consistent with the evidence in support of the corepressor model. The tumor cell line C33A can enter S phase and progress through the cell cycle even in the presence of an ectopically expressed, constitutively active pRb protein (PSM-pRb) (50). These cells do arrest in G1 however, when PSM-pRb is coexpressed with either the BRG1 protein, the AhR, or p27Kip1. Coexpression of AhR and pRb also caused a decrease in cyclin A promoter activity and cyclin A expression, and diminished both CDK2 expression and activity (50). The available evidence indicates that p27Kip1 and CDK2 are the key targets for AhR-pRb activity affecting the cell cycle, although the precise mechanism responsible for the G1 arrest mediated by AhR-pRb remains uncertain. In fact, demonstrating whether the AhR-pRb interaction functions as a coactivator or corepressor complex in cell cycle control remains a critical unresolved issue. IS THE AHR A CELL CYCLE PACEMAKER? AhR-mediated growth inhibition in the binary switch model assumes the continued presence of an AhR ligand to maintain receptor activity. Given that TCDD is resistant to metabolism ensuring a long halflife within the organism, TCDD exposure results in sustained AhR activation. In contrast, exogenous ligands such as ß-nathphoflavone or the putative endogenous ligand are readily metabolized by the CYP1A1 gene product, cytochrome P450IA1 (51). AhR activation under these circumstances is transient, due to a negative feedback signaling mechanism in which agonist-induced AhR-dependent expression of CYP1A1 results in P450IA1-catalyzed depletion of the AhR agonist. We (Figure 5) and others (52) have observed that serum treatment of quiescent (serum- starved) cells to initiate cell cycle reentry and subsequent transition into S phase, also induces CYP1A1 expression. This suggests that serum either stimulates the formation of an endogenous AhR agonist, or contains an agonist. P450IA1 induction serves to inactivate the AhR by metabolically depleting the ligand. We speculate that AhR inactivation is necessary to prevent the receptor from functioning to inhibit S phase entry. Significantly, the data reveal (Figure 5) that P450IA1
CHAPTER 26 / AhR-MEDIATED CELL CYCLE CONTROL Figure 5. P450IA1 expression is enhanced by 1-(1propynyl)pyrene (1-PP). Serum- starved 5L cells were treated with 10% serum in the absence and presence of 1 µM or 10 µM 1-(1propynyl)pyrene for the indicated period. Total cell lysates were fractionated by SDS-PAGE and probed for P450IA1, pRb and Transferrin receptor (TfR), a loading control. pRb fractionates as the more rapidly migrating hypophosphorylated active form (pRb) and slower migrating inactive hyperphosphorylated form (ppRb).
induction by serum is markedly enhanced in the presence of the P450IA1 suicide substrate 1-(1-propynyl)pyrene (1-PP) (53). The dose-dependent increase in P450IA1 protein is attributed to prolonged AhR activation resulting from inhibition of P450IA1 activity and hence, diminished clearance of the agonist. Moreover, 1-PP treatment stalls serum-stimulated entry into S phase as measured by the delay in pRb hyperphosphorylation. Additional flow cytometric studies confirmed that the 1-PP treated cells fail to enter Sphase, involving an AhR-dependent mechanism concomitant with increased p27Kip1 expression (manuscript in preparation). The increase in p27Kip1 expression is not seen in the cells treated with serum alone (data not shown) suggesting that prolonged AhR activation is essential to increase p27Kip1 expression. The exquisite CYP1A1 responsiveness following transient AhR activation is attributed to the potent CYP1A1 enhancer region comprising multiple XREs (15). In contrast, analysis of 1.6Kb of the p27Kip1 promoter sequence reveals only one candidate XRE (18), suggesting that the p27Kip1 promoter is less responsive to AhR activity necessitating prolonged AhR activation. The evidence is consistent with a mechanism in which the duration of AhR activity, and hence, expression of p27Kip1 and cell cycle entry into S phase, is controlled at least in part by cytochrome P450IA1 activity. This bestows upon the AhR the property of a cell cycle "pacemaker", responsive to environmental stimuli whether natural or man-made. Investigations with the synthetic antitumor agent 2-(4-Amino-3-methylphenyl) benzothiazole (DF 203), determined that inhibition of cell growth is inexorably linked to CYP1A1 induction and P450IA1 activity (54, 55). The antitumor property of DF 203 was tentatively attributed to a DNA damage-induced growth arrest caused by P450IA1-generated genotoxic metabolites (54). Low DF 203 concentrations (i.e., 0.1-1 µM) induce P450IA1 activity, consistent with the recent observation that DF 203 is an AhR agonist responsible for CYP1A1 induction (55). However, labeling studies revealed that metabolism of DF 203 by P450IA1 generates a reactive intermediate capable of covalently binding to the enzyme (54). Covalent coupling of the substrate presumably results in P450IA1 inactivation, and could account for enzyme inhibition detected with doses of DF 203 =10 µM (54). Therefore, the growth inhibitory action of DF 203 may actually reflect P450IA1 inactivation akin to the action of 1-PP, resulting in prolonged AhR activity. Given that structurally distinct compounds like DF 203 and 1-PP appear to curtail cell growth through a common mechanism targeting P450IA1 activity, greatly enhances 265
the scope for developing a clinically useful antitumor agent. This structural diversity amongst these inhibitory agents is entirely consistent with the broad substrate specificity exhibited by P450IA1. THE CONTINUING SEARCH PHYSIOLOGICAL AHR AGONIST FOR A
The existence and identity of naturally occurring AhR agonists has been recognized for some time. Tryptophan and indole metabolites such as indole-3carbinol found in cruciferous vegetables including broccoli and Brussels sprouts (56), bilirubin (57) and lipoxin A4 (58) will activate the AhR. However, their restricted distribution, modest potency and generally low levels disqualify them as likely physiological AhR ligands. Interest is currently focused on indirubin as an AhR agonist (59), in part because indirubin and analogs are also selective inhibitors of CDK activity (60). Indirubin is found in plant extracts used in Chinese herbal medicine (61), and in urine and serum (59). The urinary indirubin is believed to be the product of tryptophan degradation to indole by intestinal bacteria that is subsequently absorbed and metabolized in the liver to indirubin by cytochromes P450 (62). Studies using an AhR-regulated yeast-based reporter system revealed that indirubin can induce reporter gene expression with an EC50 of 200pM, approximately 50-fold lower than for TCDD in the same experimental system (59). Although direct evidence for indirubin binding by the AhR was not provided, the EC50 value is suggestive of direct receptor activation, rather than an indirect mechanism involving CDK inhibition considering that the IC50 values for kinase inhibition are 3-4 orders of magnitude greater (61). Studies examining AhR activation and CDK inhibition by indirubin in the same setting are required to confirm the relative dose dependencies however, before conclusions about the physiological importance of each signaling pathway can be drawn. While it seems premature to classify indirubin as an endogenous AhR agonist, from a therapeutic standpoint the efficacy of indirubin (or analogs) as antitumor agents is encouraging because of their ability to both directly inhibit CDK activity, and indirectly by signaling through the AhR to inhibit the cell cycle. Conceivably, combination therapies relying on the properties of indirubins and P450IA1 inhibitors may prove effective in treating various cancers.
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CONCLUDING REMARKS It is evident that AhR action can impinge directly on cell cycle regulation in response to TCDD or a putative physiological AhR ligand. The evidence suggests that under normal circumstances the AhR functions as a cell cycle pacemaker by regulating the level of P450IA1 and p27Kip1 expression. The autoregulatory feedback loop between the AhR and CYP1A1 expression can also promote cell proliferation indirectly however, genotoxins such as BaP induce AhR-mediated expression of CYP1A1 rendering BaP carcinogenic by biotransformation to BPDE. Paradoxically, TCDD can induce cell cycle arrest through persistent AhR activation, yet it is classified as a complete carcinogen by the U.S. Environmental Protection Agency. This conundrum is reconcilable if we assume that the tumor promoting property of TCDD reflects sustained expression of CYP1A1 increasing the likelihood of a deleterious DNA lesion caused by P450IA1-generated metabolites. Recent reports suggest that the AhR may also contribute more directly to a proliferative response, by inducing the c-Myc proto-oncogene in a RelA-dependent process in human breast cells (63), or c-Ha-ras through a redox-sensitive mechanism in vascular smooth muscle cells (64). Both are suggestive of cross-talk with other signaling pathways. It is prudent to keep in mind too, that signaling pathways not discussed in this chapter nevertheless can also regulate AhR levels and activity. These include the involvement of protein kinase C and mitogenactivated kinases (65-69), ubiquitin-mediated AhR degradation (70, 71), coactivator interactions (72-74), and the AhR repressor protein (75). Modulation of AhR-mediated cell cycle control by these signaling pathways remains to be explored. ACKNOWLEDGEMENTS The author wishes to acknowledge the excellent technical support provided by Aviva Levine. Preparation of this chapter and cited research performed in the author's laboratory was supported by the NIEHS Grant R01 ES07800. REFERENCES 1. 2. Pelkonen, O. and Nebert, N.W. (1982) Pharmacol Rev 34, 189-222. Ramet, M., Castren, K., Jarvinen, K., Pekkala, K., Turpeenniemi-Hujanen, T., Soini, Y., Paakko, P. and Vahakangas, K. (1995) Carcinogenesis 16, 2117-2124. Shimizu, Y., Nakatsuru, Y., Ichinose, M., Takahashi, Y., Kume, H., Mimura, J., FujiiKuriyama, Y. and Ishkawa, T. (2000) Proc Natl Acad Sci USA 97, 779-782. Poland, A. and Knudson, J.C. (1982) Annu Rev Pharmacol Toxicol 22, 517-554. Matikainen, T., Perez, G.I., Jurisicova, A., Pru, J.K., Schlezinger, J.J., Ryu, H.Y., Laine, J., Sakai, T., Korsmeyer, S.J., Casper, R.F., Sherr, D.H., Tilly, J.L. (2001) Nat Genet 28, 355-360 Schmidt, J.V. and Bradfield, C.A. (1996) Annu Rev 266 7. 8. 9.
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