Biomedical subjects

Alvaro Puga

Publications and source records attributed to Alvaro Puga.

At least 19 recordsLinked to original sources

PubMed2006

Long term low-dose arsenic exposure induces loss of DNA methylation.

Arsenic ranks as the number one toxic environmental contaminant. In humans, arsenic exposure is associated with various forms of cancer, cardiovascular and skin diseases, neuropathies of the central nervous system, and genotoxic and immunotoxic effects. Although a well recognized human carcinogen, arsenic itself is not a potent mutagen and has been thought to act through epigenetic mechanisms that modify DNA methylation patterns, perhaps in conjunction with DNA-damaging agents. To develop preliminary support for a more thorough examination of this hypothesis, we have measured the effect of submicromolar and low-micromolar concentrations of arsenite on the methylation status of DNA and the biochemical reactions that regulate it. We find that arsenic causes the depletion of S-adenosylmethionine, the main cellular methyl donor, and represses the expression of the DNA methyltransferase genes DNMT1 and DNMT3A. Possibly as a consequence of these two complementary mechanisms, long-term exposure to arsenic results in DNA hypomethylation.

Arsenites↗

PubMed2006

Naphthalene toxicity in mice and aryl hydrocarbon receptor-mediated CYPs.

Naphthalene (NP) has been designated a "reasonably anticipated human carcinogen" because of positive responses in carcinogenicity bioassays in rodents. Whereas CYP2F enzymes are widely regarded as responsible for NP bioactivation, other metabolic enzymes--including CYP1A1 and CYP1A2--produce NP-1,2-oxide in vitro. We investigated the role of these aryl hydrocarbon receptor (AHR)-mediated enzymes in NP toxicity in two ways. First, NP was assessed for the ability to activate transcription via the AHR in an in vitro luciferase reporter assay and was found to have no activity. Second, mice deficient in AHR, CYP1A1 or CYP1A2 were dosed with NP alone, or following pretreatment with the CYP2F inhibitor 5-phenyl-1-pentyne. None of the knockout mice were protected from olfactory toxicity of NP. In contrast, CYP1A1- and CYP1A2-null mice pretreated with 5-phenyl-1-pentyne exhibited no NP olfactory toxicity. These results suggest that AHR-mediated enzymes do not contribute significantly to NP bioactivation in the intact animal.

Alkynes↗

PubMed2005

Aryl hydrocarbon receptor, cell cycle regulation, toxicity, and tumorigenesis.

Most effects of exposure to halogenated and polycyclic aromatic hydrocarbons are mediated by the aryl hydrocarbon receptor (AHR). It has long been recognized that the AHR is a ligand-activated transcription factor that plays a central role in the induction of drug-metabolizing enzymes and hence in xenobiotic detoxification. Of late, it has become evident that outside this well-characterized role, the AHR also functions as a modulator of cellular signaling pathways. In this Prospect, we discuss the involvement of the AHR in pathways critical to cell cycle regulation, mitogen-activated protein kinase cascades, immediate-early gene induction, and the functions of the RB protein. Ultimately, the toxicity of AHR xenobiotic ligands may be intrinsically connected with the perturbation of these pathways and depend on the many critical signaling pathways and effectors with which the AHR itself interacts.

Animals↗

PubMed2005

Impact of Cyp1a2 or Ahr gene knockout in mice: implications for biomonitoring studies.

UNLABELLED: Studies of the impact of phase 1 enzyme polymorphisms on genetic damage have yielded mixed results. We studied how genetic damage would be altered when specific genes were ablated under low dose conditions. METHODS: Knockouts (KO) were generated from c57bl6/J mice with mutations in Cyp1a2 or Ahr receptor that eliminated gene product function. Animals were treated topically with either 4-aminobiphenyl (4ABP) 10mg/kg, benzo(a)pyrene (BaP) 33.3mg/kg or dibenzo(c,g)carbazole (DBC) 8 mg/kg, and sacrificed after 24h. DNA from livers, skin and/or urinary bladders were isolated and (32)P-post labelled. RESULTS: Cyp1a2-/- mice did not differ in 4ABP DNA adduct levels in either urinary bladder or liver compared to wildtype. There was a sex difference in the organ affected. Cyp1a2 knockout reduced skin BAP adduct levels 50% and AHR knockout reduced skin BAP adduct levels by 90%. There was no impact of either knockout on the levels of DBC-DNA adducts in any tissue. CONCLUSIONS: Ablation of specific metabolizing enzymes had compound- and tissue-specific effects in mice. Phenotypic variability in single CYP enzymes may have minor impact in humans at low doses, but variation in the ability to induce the family of CYPs may have a greater impact.

Aminobiphenyl Compounds↗

PubMed2005

Gene expression profiling reveals novel regulation by bisphenol-A in estrogen receptor-alpha-positive human cells.

Bisphenol-A (BPA) shows proliferative actions in uterus and mammary glands and may influence the development of male and female reproductive tracts in utero or during early postnatal life. Because of its ability to function as an estrogen receptor (ER) agonist, BPA has the potential to disrupt normal endocrine signaling through regulation of ER target genes. Some genes are regulated by both estradiol (E2) and BPA, but those exclusive to either agent have not been described. Using a yeast strain incorporating a vitellogenin A2 ERE-LacZ reporter gene into the genome, we found that BPA induced expression of the reporter in colonies transformed with the ERalpha expression plasmid, illustrating BPA-mediated regulation within a chromatin context. Additionally, a reporter gene transiently transfected into the endometrial cancer (Ishikawa) cell line also showed BPA activity, although at 100-fold less potency than E2. To compare global gene expression in response to BPA and E2, we used a variant of the MCF-7 breast cancer cell line stably expressing HA-tagged ERalpha. Cultures were treated for 3h with an ethanol vehicle, E2 (10(-8)M), or BPA (10(-6)M), followed by isolation of RNA and microarray analysis with the human U95A probe array (Affymetrix, Santa Clara, CA, USA). More than 300 genes were changed 2-fold or more by either or both agents, with roughly half being up-regulated and half down-regulated. A number of growth- and development-related genes, such as HOXC1 and C6, Wnt5A, Frizzled, TGFbeta-2, and STAT inhibitor 2, were found to be affected exclusively by BPA. We used quantitative real-time PCR to verify regulation of the HOXC6 gene, which showed decreased expression of approximately 2.5-fold by BPA. These results reveal novel effects by BPA and E2, raising interesting possibilities regarding the role of endocrine disruptors in sexual development.

Benzhydryl Compounds↗

PubMed2005

Butylhydroquinone protects cells genetically deficient in glutathione biosynthesis from arsenite-induced apoptosis without significantly changing their prooxidant status.

Arsenic, first among the top environmentally hazardous substances, is associated with skin, lung, liver, kidney, prostate, and bladder cancer. Arsenic is also a cardiovascular and a central nervous system toxicant, and it has genotoxic and immunotoxic effects. Paradoxically, arsenic trioxide is used successfully in the treatment of acute promyelocytic leukemia and multiple myeloma. Arsenic induces oxidative stress, and its toxicity is decreased by free thiols and increased by glutathione depletion. To further characterize the role of glutathione and oxidative stress in the toxicity of arsenic, we have used fetal fibroblasts from Gclm(-/-) mice, which lack the modifier subunit of glutamate-cysteine ligase, the rate-limiting enzyme in glutathione biosynthesis. Gclm(-/-) mouse embryo fibroblasts (MEFs) are eight times more sensitive to arsenite-induced apoptotic death. Because of a dramatic decrease in glutathione levels, Gclm(-/-) MEFs have a high prooxidant status that is not significantly relieved by treatment with the phenolic antioxidant tBHQ; however, tBHQ blocks arsenite-induced apoptosis in both Gclm(+/+) and Gclm(-/-) cells, although it raises a significant antioxidant response only in Gclm(+/+) cells. Global gene expression profiles indicate that tBHQ is significantly effective in reversing arsenite-induced gene deregulation in Gclm(+/+) but not in Gclm(-/-) MEFs. This effect of tBHQ is evident in the expression of metalloproteases and chaperones, and in the expression of genes involved in DNA damage and repair, protein biosynthesis, cell growth and maintenance, apoptosis, and cell cycle regulation. These results suggest that regulation of glutathione levels by GCLM determines the sensitivity to arsenic-induced apoptosis by setting the overall ability of the cells to mount an effective antioxidant response.

Animals↗

PubMed2005

Arsenite-induced aryl hydrocarbon receptor nuclear translocation results in additive induction of phase I genes and synergistic induction of phase II genes.

Complex mixtures of carcinogenic metalloids, such as arsenic, and polycyclic aromatic hydrocarbons or halogenated aromatic hydrocarbons are common environmental contaminants. The biological consequences of exposure to these mixtures are unpredictable and, although the health effects of individual chemicals may be known, the toxicity of environmental mixtures is largely unexplored. Arsenic, not a potent mutagen by itself, is co-mutagenic with many DNA-damaging agents. Mixtures of arsenite plus benzo[a]pyrene (B[a]P) augment B[a]P mutagenicity, suggesting that arsenite might uncouple expression of phase I and II genes responsible for detoxification. We have studied the effects of arsenite exposure on the activation of the aryl hydrocarbon receptor (AHR) and its subsequent role in gene transactivation. Treatment of mouse Hepa-1 cells with arsenite induces AHR nuclear translocation and binding to the Cyp1a1 gene promoter with the same efficiency as tetrachlorodibenzo-p-dioxin (TCDD), the most potent ligand of the AHR; however, TCDD and B[a]P are an order of magnitude more potent than arsenite in up-regulating Cyp1a1 transcription. Global profiling analyses of cells treated with arsenite plus B[a]P indicate that several phase I and II detoxification genes are in some cases additively and in others synergistically deregulated by the mixtures. Real-time reverse transcription-polymerase chain reaction analyses of mouse embryonic fibroblasts showed that the mixtures had an additive effect on the mRNA levels of Cyp1b1, a prototypical phase I detoxification gene, and an AHR-dependent synergistic effect on the corresponding levels of Nqo1, a prototypical phase II gene. We conclude that exposure to arsenite/B[a]P mixtures causes regulatory changes in the expression of detoxification genes that ultimately affect the metabolic activation and disposition of toxicants.

Active Transport, Cell Nucleus↗

PubMed2004

Ah receptor signals cross-talk with multiple developmental pathways.

For many years, the Ah receptor (AHR) has been a favorite of toxicologists and molecular biologists studying the connections between genes and the changes in the control of gene expression resulting from environmental exposures. Much of the attention given to the Ah receptor has focused on the nature of its ligands, many of which are known or suspected carcinogens, and on the role that its best studied regulatory product, the CYP1A1 enzyme, plays in toxic responses and carcinogen activation. This understandable bias has resulted in a disproportionate amount of Ah receptor research being directed at toxicological or adaptive end points. In recent times, it has become evident that Ah receptor functions are also involved in molecular cascades that lead to inhibition of proliferation, promotion of differentiation, or apoptosis, with an important bearing in development. Developmental and toxicological AHR functions may not always be related. The ancestral AHR protein in invertebrates directs the developmental fate of a few specific neurons and does not bind xenobiotic ligands. The mammalian AHR maintains normal liver function in the absence of exogenous ligands and, when activated by dioxin, cross-talks with morphogenetic and developmental signals. Toxic end points, such as the induction of cleft palate by dioxin in mice embryos, might be at the crossroads of these signals and provide important clues as to the developmental role of the AHR.

Animals↗

PubMed2004

A critical role for MAP kinases in the control of Ah receptor complex activity.

The heterodimeric complex of aromatic hydrocarbon receptor (AHR) and Ah receptor nuclear translocator (ARNT) plays a pivotal role in controlling the expression of drug metabolism genes, such as the cytochromes p450 (Cyp) 1a1 and 1b1, believed to be responsible for most toxic effects of the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In this study, we show that activation of Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) modulates ARNT transcription activity and potentiates the transcriptional activity of AHR/ARNT complexes. Inhibition of ERK by chemical compounds and ablation of JNK caused significant decreases in CYP1A1 induction by TCDD. Compared to wild type, JNK2 ablation significantly reduced TCDD-stimulated CYP1A1 expression in mouse thymus and testis, but not in liver. In contrast, CYP1B1 expression was unaffected in all three tissues of the knockout mice. These data suggest that JNK and ERK modulate ARNT activity and AHR/ARNT-dependent gene expression, contributing to the gene-specific and tissue-specific toxicity of environmental contaminants.

Animals↗

PubMed2004

Bisphenol-A and estradiol exert novel gene regulation in human MCF-7 derived breast cancer cells.

Xenoestrogens such as bisphenol-A (BPA) can mimic endogenous 17beta-estradiol (E2) in vitro and in vivo through binding the estrogen receptor (ER), and modulating target gene expression. In the present study, we compared global gene regulation by BPA and E2 in estrogen responsive (ERalpha-HA) human breast cancer cells derived from the MCF-7 cell line. The ERalpha-HA cells (stably over-expressing ERalpha) were exposed to E2 (10(-8)M) or BPA (10(-6)M), for 3h followed by analysis of global gene expression. More than 40 transcripts were significantly changed in ERalpha-HA cells, with many being unique to BPA. At least 15 genes were modulated by BPA in the ER-null C4-12 cell line, indicating ER independent activity. Utilizing quantitative reverse transcription-polymerase chain reaction (RT-PCR), we confirmed BPA and E2 mediated regulation of four selected genes. A consensus Alu-type estrogen responsive element (ERE) was found in the Wiskott-Aldrich syndrome protein (WASP) gene, which conferred responsiveness to BPA and E2 in a reporter gene assay. Significant stimulation was seen only in ERalpha expressing cells, thus indicating a functional ERE. Taken together these data illustrate novel gene regulation by BPA and E2, which has implications for in vivo actions and previous reports of additive and synergistic effects on breast cancer cell growth.

Alu Elements↗

PubMed2004

The aryl hydrocarbon receptor displaces p300 from E2F-dependent promoters and represses S phase-specific gene expression.

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes a wide range of toxic, teratogenic, and carcinogenic effects. TCDD is a ligand for the aromatic hydrocarbon receptor (AHR), a ligand-activated transcription factor believed to be the primary mediator of these effects. Activation of the AHR by TCDD also elicits a variety of effects on cell cycle progression, ranging from proliferation to arrest. In this report, we have characterized further the role of the activated AHR in cell cycle regulation. In human mammary carcinoma MCF-7 and mouse hepatoma Hepa-1 cells, TCDD treatment decreased the number of cells in S phase and caused the accumulation of cells in G(1). In Hepa-1 cells, this effect correlated with the transcriptional repression of several E2F-regulated genes required for S phase progression. AHR-mediated gene repression was dependent on its interaction with retinoblastoma protein but was independent of its transactivation function because AHR mutants lacking DNA binding or transactivation domains repressed E2F-dependent expression as effectively as wild type AHR. Overexpression of p300 suppressed retinoblastoma protein-dependent gene repression, and this effect was reversed by TCDD. Chromatin immunoprecipitation assays showed that TCDD treatment caused the recruitment of AHR to E2F-dependent promoters and the concurrent displacement of p300. These results delineate a novel mechanism whereby the AHR, a known transcriptional activator, also mediates gene repression by pathways involving combinatorial interactions at E2F-responsive promoters, leading to the repression of E2F-dependent, S phase-specific genes. The AHR seems to act as an environmental checkpoint that senses exposure to environmental toxicants and responds by signaling cell cycle inhibition.

Animals↗

PubMed2004

Retention of Cr(III) by high-performance chelation ion chromatography interfaced to inductively-coupled plasma mass spectrometric detection with collision cell.

High-performance chelation ion chromatography (HPCIC) was employed to retain cationic Cr(III) on an anion-exchange column and hence allow the separation of the two most prevalent forms of chromium, Cr(II) and Cr(VI). A mobile phase of nitric acid was utilized at pH = 1.5; additionally, 2,6-pyridinedicarboxylic acid was used at a concentration of 6 mM. Additives with different structural characteristics were used in an effort to elucidate retention mechanisms. Inductively-coupled plasma mass spectrometry was used for chromium detection. A collision cell was utilized to reduce chloride-based polyatomic ions that may interfere with the detection of Cr(III), and a detection limit study yielded levels in the low part-per-billion range. The newly developed method was applied to the chromatographic analysis of samples of an incubation medium containing Cr(VI) incubated with cell nuclei.

Animals↗

PubMed2004

Expression of genes in the TGF-beta signaling pathway is significantly deregulated in smooth muscle cells from aorta of aryl hydrocarbon receptor knockout mice.

The molecular basis for the adverse biological effects of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD), a pervasive environmental toxin, is largely unknown. TCDD is a ligand for the cytosolic aromatic hydrocarbon receptor (AHR) which mediates the transcriptional induction of the xenobiotic metabolizing genes in the CYP1 family of cytochromes P450. Previous studies have suggested that the AHR may carry out important functions in the cell in addition to metabolizing toxins. We present gene expression profiles of smooth muscle cells from wild type and Ahr(-/-) mice that show significant changes in the RNA levels of the transforming growth factor-beta3 (Tgfb3) gene and genes involved in the modulation and processing of TGF-beta. The RNA expression profiles support a hypothesis that in the wild type, the AHR represses Tgfb gene expression and affects the gene expression of several TGF-beta-modulating and processing genes. We also observed that RNA levels increased for TGF-beta2, CYP1b1, and TGF-beta-related genes in Ahr(-/-) smooth muscle cells exposed to TCDD. These data are consistent with a hypothesis that TCDD stimulates the TGF-beta2 signaling pathway in the absence of the AHR to activate the Cyp1b1 gene. The above results provide a possible explanation for some of the multiple biological effects of TCDD and the physiological role played by the AHR in the absence of environmental agents.

Animals↗

PubMed2004

2,3,7,8-Tetrachlorodibenzo-p-dioxin blocks androgen-dependent cell proliferation of LNCaP cells through modulation of pRB phosphorylation.

Cell-cycle regulatory events associated with inhibition of androgen-dependent cell proliferation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were studied in the human-derived LNCaP cell line. TCDD blocked the G(1) to S transition of LNCaP cells synchronized in G(0)/G(1) when these cells were induced to reinitiate cell-cycle progression by dihydrotestosterone (DHT). Western blot analyses of these cells revealed altered expression levels of G(1) regulatory proteins, including increases in hypophosphorylated retinoblastoma protein and concomitant decreases in cyclin D1. p21(WAF1/CIP1), which is involved in the assembly of cyclin D1/cyclin-dependent kinase-4 complexes, was increased by DHT or TCDD when each compound was administered singly but was reduced to background levels in cells simultaneously treated with DHT and TCDD. Reporter gene assays revealed the presence of several Ah receptor response-element motifs in the promoter and first intron of the p21(WAF1/CIP1) gene that respond to TCDD-mediated Ah receptor activation independently of p53. Transcription studies showed that activation of aryl hydrocarbon receptor blocks androgen-dependent gene induction in LNCaP cells as well as in African green monkey CV-1 cells. These data point to at least two mechanisms whereby TCDD blocks androgen receptor function: 1) by blocking androgen-induced cell proliferation through modulation of the expression and activities of regulatory proteins controlling cell-cycle progression; and 2) by squelching androgen receptor-mediated gene transcription through receptor cross-talk, possibly involving competition for coregulators or by direct protein interaction.

Androgens↗

PubMed2004

Different global gene expression profiles in benzo[a]pyrene- and dioxin-treated vascular smooth muscle cells of AHR-knockout and wild-type mice.

Benzo[a]pyrene (B[a]P) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are potent ligands for the aryl hydrocarbon receptor (AHR). High-density oligonucleotide microarrays were used to generate global gene expression profiles of wild-type and Ahr(-/-) vascular smooth muscle cells (SMCs) from mouse aorta. To determine whether there are signaling pathways other than the AHR involved in B[a]P metabolism, wild-type and AHR knockout (Ahr(-/-) SMCs were exposed to B[a]P. Two signaling pathways, represented by TGF-beta2 and IGF-1, were identified as potential candidates of an AHR alternate pathway for cells to respond to B[a]P. The wild-type SMCs responded similarly to B[a]P and TCDD in the regulation of a small set of common genes known to respond to the activated AHR (e.g., glutamine S-transferase). However, wild-type SMCs responded in a way that involves many additional genes, suggesting that a very divergent cellular response may be involved when SMCs are exposed to the two classic inducers of the AHR. In contrast, many more genes in the Ahr(-/-) cells responded similarly to B[a]P and TCDD, including Cyp1b1, than responded differently, which indicates that eliminating the AHR is effective for investigating potential alternate cellular mechanisms that respond to B[a]P and TCDD.

Animals↗

PubMed2004

Gene expression profiles of mouse aorta and cultured vascular smooth muscle cells differ widely, yet show common responses to dioxin exposure.

Exposure to environmental toxicants may play a role in the onset and progression of cardiovascular disease. Many environmental agents, such as dioxin, are risk factors for atherosclerosis because they may exacerbate an underlying disease by altering gene expression patterns. Expression profiling of vascular tissues allows the simultaneous analysis of thousands of genes and may provide predictive information particularly useful in early disease stages. Often, however, in vivo experiments are unfeasible for material or ethical reasons, and data from cultured cells must be used instead, even though it may not be known whether cultured cells and live tissues share common global responses to the same toxicant. In a search for genes responsive to dioxin exposure, we used oligonucleotide microarrays with DNA sequences from 13,433 genes to compare global gene expression profiles of C57BL/6 mice aortas with cultured vascular smooth muscle cells (vSMCs) of the same mice. Aorta segments and vSMCs differed in the expression of more than 4500 genes, many showing expression differences greater than 1000-fold. Integration of microarray data into Gene Ontology Project annotations showed that many of the genes differentially expressed belonged to the same biological process or metabolic pathway. Notwithstanding these results, a subset of 35 genes responded in the same fashion to dioxin exposure in both systems. Genes in this subset encoded phase I and phase II detoxification enzymes, signal transduction kinases and phosphatases, and proteins involved in DNA repair and the cell cycle. We conclude that vSMCS may be useful aorta surrogates to study early gene expression responses to dioxin exposure, provided that analyses focus on this subset of genes.

Animals↗

PubMed2003

Chromium inhibits transcription from polycyclic aromatic hydrocarbon-inducible promoters by blocking the release of histone deacetylase and preventing the binding of p300 to chromatin.

Co-contamination with complex mixtures of carcinogenic metals, such as chromium, and polycyclic aromatic hydrocarbons is a common environmental problem with multiple biological consequences. Chromium exposure alters inducible gene expression, forms chromium-DNA adducts and chromium-DNA cross-links, and disrupts transcriptional activator-co-activator complexes. We have shown previously that exposure of mouse hepatoma Hepa-1 cells to chromate inhibits the induction of the Cyp1a1 and Nqo1 genes by dioxin. Here we have tested the hypothesis that chromium blocks gene expression by interfering with the assembly of productive transcriptional complexes at the promoter of inducible genes. To this end, we have studied the effects of chromium on the expression of genes induced by benzo[a]pyrene (B[a]P), another aryl hydrocarbon receptor agonist, and characterized the disruption of Cyp1a1 transcriptional induction by chromium. Gene expression profiling by using high density microarray analysis revealed that the inhibitory effect of chromium on B[a]P-dependent gene induction was generalized, affecting the induction of over 50 different genes involved in a variety of signaling transduction pathways. The inhibitory effect of chromium on Cyp1a1 transcription was found to depend on the presence of promoter-proximal sequences and not on the cis-acting enhancer sequences that bind the aryl hydrocarbon receptor-aryl hydrocarbon receptor nuclear translocator complex. By using transient reporter assays and chromatin immunoprecipitation analyses, we found that chromium prevented the B[a]P-dependent release of HDAC-1 from Cyp1a1 chromatin and blocked p300 recruitment. These results provide a mechanistic explanation for the observation that chromium inhibits inducible but not constitutive gene expression.

Animals↗

PubMed2002

Role of the aryl hydrocarbon receptor in cell cycle regulation.

One of the most puzzling aspects of the biological impact of polycyclic aromatic hydrocarbon compounds is that they elicit an apparently unrelated variety of toxic, teratogenic, and carcinogenic responses in exposed animals and in humans. At the cellular level, these environmental toxicants affect cell cycle regulatory mechanisms and signal transduction pathways in ways that are equally diverse and often contradictory. For example, depending on the particular cell lines studied, exposure to these compounds may lead to cell proliferation, to terminal differentiation, or to apoptosis. These effects are mediated by the aryl hydrocarbon receptor, a ligand-activated transcription factor well known for its regulatory activity on the expression of several phase I detoxification cytochrome P450 genes. Research into the molecular mechanisms of aryl hydrocarbon receptor function has uncovered a novel role for this protein during cell cycle progression. The activated receptor acts as an environmental sensor and cell cycle checkpoint that commits cells exposed to adverse environmental stimuli to arrest before the onset of DNA replication.

Animals↗