Comparison of effects of direct‐acting DNA methylating and ethylating agents on inducible gene expression in vivo

McCaffrey, Jennifer; Hamilton, Joshua W.

doi:10.1002/em.2850230303

Cited by 14 publications

(9 citation statements)

References 52 publications

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“…Our results to date [Hamilton and Wetterhahn, 1989;Hamilton et al, 1993;McCaffrey and Hamilton, 1994b;McCaffrey et al, 19941, taken together with previous results in other systems [Wogan and Friedman, 1968;Kensler et al, 1976a,b;Gayda and Pariza, 1983;Yeoh et al, 1983;Huang et al, 1984;Miller and Wogan, 19861, strongly support the general hypothesis that inducible gene expression is a target for carcinogen-induced DNA damage in vivo. However, the mechanistic basis for these effects is not yet clear.…”

Section: Discussionsupporting

confidence: 87%

“…We have previously examined the DNA crosslinking agent and human lung carcinogen, chromium(V1) [Hamilton and Wetterhahn, 19891, several direct-acting, simple alkylating agents [McCaffrey and Brookes, 1982;Kurian ei al., 1985;Marrot et al, 1987;Kootstra et al, 1989;Moyer et al, 19891 and highest levels of genomic organization rArrand and Murray, I9g2;yu, 1983a9b;Gupta9 1984;Obi et 19881. What is still far less clear is whether chemically induced DNA damage is non-randomly distributed at the Hamilton, 1994b], and several carcinogens that induce bulky monoadduct lesions in DNA [Hamilton et al, 19931 for their effects on constitutive and inducible gene expression. All of these carcinogens altered both the basal and inducible expression of several model inducible genes, whereas none of these same treatments had an effect on the expression of several constitutively expressed genes.…”

Section: Introductionmentioning

confidence: 99%

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Preferential effects of the chemotherapeutic DNA crosslinking agent mitomycin C on inducible gene expression in vivo

Caron¹,

Hamilton²

1995

Environ and Mol Mutagen

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The immediate effects of a single dose of the chemotherapeutic DNA crosslinking agent, mitomycin C (MMC), on the expression of several constitutive and drug-inducible genes were examined in a simple in vivo system, the 14 day chick embryo. We observed no effect of MMC on the steady-state mRNA expression of the constitutively expressed beta-actin, transferrin, or albumin genes. In contrast, MMC treatment significantly altered both the basal and drug-inducible mRNA expression of two glutethimide-inducible genes, 5-aminolevulinic acid (ALA) synthase and cytochrome P450 CYP2H1. The basal expression of these genes was transiently but significantly increased over a 24 hr period following a single dose of MMC. Conversely, MMC significantly suppressed the glutethimide-inducible expression of these genes when administered 1 to 24 hr prior to the inducing drug. The effects of MMC on both basal and drug-inducible ALA synthase and CYP2H1 mRNA expression were principally a result of changes in the transcription rates of these genes. In contrast, MMC treatment had little or no effect on glutethimide-induced expression of ALA synthase or CYP2H1 when administered 1 hr after the inducing drug, suggesting that a very early event in the induction process represents the target for these MMC effects. Covalent binding studies demonstrated that the effects of MMC on gene expression were closely correlated temporally with formation of [3H]-porfiromycin-DNA adducts. These results support the hypothesis that genotoxic chemicals specifically target their effects to inducible genes in vivo.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Preferential effects of the chemotherapeutic DNA crosslinking agent mitomycin C on inducible gene expression in vivo

Caron¹,

Hamilton²

1995

Environ and Mol Mutagen

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“…In contrast, none of the constitutively expressed genes tested (p-actin, transferrin, albumin, and ax-tubulin) were responsive. Effects on inducible gene expression have been observed in both the rat and chick embryo in vivo (10,13,34,55,59) and in primary chick embryo, adult rat, and rat embryo hepatocytes and rat hepatoma cell lines in culture (56)(57)(58). All of these systems show similar responses.…”

Section: Discussionmentioning

confidence: 98%

Molecular basis for effects of carcinogenic heavy metals on inducible gene expression.

Hamilton

Kaltreider

Bajenova

et al. 1998

Environ Health Perspect

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Certain forms of the heavy metals arsenic and chromium are considered human carcinogens, although they are believed to act through very different mechanisms. Chromium(VI) is believed to act as a classic genotoxic and mutagenic agent, and DNANchromatin appears to be the principal target for its effects. In contrast, arsenic(lll) is considered nongenotoxic, but is able to target specific cellular proteins, principally through sulfhydryl interactions. We had previously shown that various genotoxic chemical carcinogens, including chromium(VI), preferentially altered expression of several inducible genes but had little or no effect on constitutive gene expression. We were therefore interested in whether these carcinogenic heavy metals might target specific but distinct sites within cells, leading to alterations in gene expression that might contribute to the carcinogenic process. Arsenic(lll) and chromium(V1) each significantly altered both basal and hormone-inducible expression of a model inducible gene, phosphoenolpyruvate carboxykinase (PEPCK), at nonovertly toxic doses in the chick embryo in vivo and rat hepatoma H411E cells in culture. We have recently developed two parallel cell culture approaches for examining the molecular basis for these effects. First, we are examining the effects of heavy metals on expression and activation of specific transcription factors known to be involved in regulation of susceptible inducible genes, and have recently observed significant but different effects of arsenic(lll) and chromium(Vl) on nuclear transcription factor binding. Second, we have developed cell lines with stably integrated PEPCK promoter-luciferase reporter gene constructs to examine effects of heavy metals on promoter function, and have also recently seen profound effects induced by both chromium(V1) and arsenic(lil) in this system. These model systems should enable us to be able to identify the critical cis (DNA) and trans (protein) cellular targets of heavy metal exposure leading to alterations in expression of specific susceptible genes. It is anticipated that such information will provide valuable insight into the mechanistic basis for these effects as well as provide sensitive molecular biomarkers for evaluating human exposure. Environ Health Perspect 1 06(Suppl 4):1 005-1015 (1998). http://ehpnet1.niehs.nih.gov/docs/1998/Suppl4/ 1005-1015hamilton/abstract.html

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“…The regulation of this gene has been well characterized at both the physiological and molecular levels (10), and it is therefore an excellent model for examining mechanisms of gene regulation and their perturbation by toxic agents. Previous work in our laboratory demonstrated that toxin effects on PEPCK mRNA expression were primarily a result of changes in gene transcription rates (11). Effects of arsenic on PEPCK expression may also provide important clues as to how these toxic metals perturb homeostatic mechanisms, which may contribute to their overall toxicity.…”

mentioning

confidence: 89%

Arsenic alters the function of the glucocorticoid receptor as a transcription factor.

Kaltreider

Davis

Lariviere

et al. 2001

Environ Health Perspect

230

131

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Chronic human exposure to nonovertly toxic doses of arsenic is associated with an increased risk of cancer. Although its carcinogenic mechanism is still unknown, arsenic does not directly cause DNA damage or mutations and is therefore thought to act principally as a co-mutagen, co-carcinogen, and/or tumor promoter. Previous studies in our laboratory demonstrated that effects of low-dose arsenic (III) (arsenite) on expression of the hormone-regulated phosphoenolpyruvate carboxykinase (PEPCK) gene were strongly associated with the glucocorticoid receptor (GR)-mediated regulatory pathway. We therefore examined specifically the effects of arsenite on the biochemical function of GR in hormone-responsive H4IIE rat hepatoma cells. Completely noncytotoxic arsenite treatments (0.3-3.3 microM) significantly decreased dexamethasone-induced expression of transiently transfected luciferase constructs containing either an intact hormone-responsive promoter from the mammalian PEPCK gene or two tandem glucocorticoid response elements (GRE). Western blotting and confocal microscopy of a green fluorescent protein-tagged-GR fusion protein demonstrated that arsenite pretreatment did not block the normal dexamethasone-induced nuclear translocation of GR. These data indicate that nontoxic doses of arsenite can interact directly with GR complexes and selectively inhibit GR-mediated transcription, which is associated with altered nuclear function rather than a decrease in hormone-induced GR activation or nuclear translocation.

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Comparison of effects of direct‐acting DNA methylating and ethylating agents on inducible gene expression in vivo

Cited by 14 publications

References 52 publications

Preferential effects of the chemotherapeutic DNA crosslinking agent mitomycin C on inducible gene expression in vivo

Preferential effects of the chemotherapeutic DNA crosslinking agent mitomycin C on inducible gene expression in vivo

Molecular basis for effects of carcinogenic heavy metals on inducible gene expression.

Arsenic alters the function of the glucocorticoid receptor as a transcription factor.

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