Metallothionein mRNA expression in mice homozygous for chromosomal deletions around the albino locus.

DeFranco, Donald B.; Morris, Sidney M.; Leonard, Claire M.; Gluecksohn-Waelsch, Salome

doi:10.1073/pnas.85.4.1161

Cited by 26 publications

(19 citation statements)

References 27 publications

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“…Action of these deleted genes, referred to as hepatocyte-specific developmental regulators (hsdr), is essential in the process that confers competence for hormone-inducible gene expression on the target genes in the liver. Interestingly, one of the glucocorticoid responsive structural genes affected in hepatocytes by the deletions is Metallothionein-1 (Mt-i), which remains normally inducible in intestinal cells of deletion homozygotes, emphasizing the cell type-specific effects of the deletions (2). In contrast to the failure of inducible gene expression in hepatocytes of mice homozygous for the deletions, constitutive gene expression remains normal (3).…”

Section: Introductionmentioning

confidence: 98%

The glucocorticoid hormone signal transduction pathway in mice homozygous for chromosomal deletions causing failure of cell type-specific inducible gene expression.

DeFranco

Bali

Torres

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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Wild-type newborn mice are characterized by the ability of certain liver-specific genes encoding various enzymes and mapping on different chromosomes to respond to glucocorticoid induction. Newborn mice homozygous for deletions at and around the albino locus on chromosome 7 fail to develop this competence for hormone-inducible gene expression even though they do show normal constitutive expression of the same genes. Studies of the glucocorticoid hormone signal transduction pathway reported here show identical expression of glucocorticoid receptor mRNA and protein in deletion homozygotes and normal littermates. Furthermore, the receptor interacts normally with the 90-kDa heat shock protein hsp9O. Elevated glucocorticoid hormone levels in newborn deletion homozygotes, most likely resulting from their stressed condition, provide an explanation for the reduced binding activities of receptors reported previously. The elimination of receptors and hormones as direct targets of the chromosomal deletion effects suggests that the failure of inducible gene expression might reside in defective competence of the affected structural genes to respond to the hormonal stimulus.

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Section: Introductionmentioning

confidence: 98%

The glucocorticoid hormone signal transduction pathway in mice homozygous for chromosomal deletions causing failure of cell type-specific inducible gene expression.

DeFranco

Bali

Torres

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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“…It is therefore conceivable, although quite unlikely, that the elevated expression of Nmo-1 mRNA (47), Aldh-1 mRNA, and Ugt-1 and Gt-1 enzyme activities (40,41), as well as the decreased expression of the four genes described above (42)(43)(44)(45)(46), might represent the action of the same gene that is missing in the 14CoS/14CoS deleted chromosomal region. We have indirect evidence suggesting that this is not, however, the case.…”

Section: Radiation Deletion Mouse Linesmentioning

confidence: 99%

“…Inbred mouse lines with overlapping radiation-induced chromosomal deletions involving the albino locus (c) on chromosome 7 have been examined, and indirect evidence has been found for regulatory genes located within the missing region of deletion homozygote mice (40)(41)(42)(43)(44)(45)(46). These regulatory loci appear to encode transacting factors that modulate the basal and inducible expression of genes that are located on other chromosomes.…”

Section: Radiation Deletion Mouse Linesmentioning

confidence: 99%

“…These regulatory loci appear to encode transacting factors that modulate the basal and inducible expression of genes that are located on other chromosomes. In most cases these genes are downregulated about 2-to 4-fold in the deletion homozygote (C14Cos/ c14COS), while the wild-type (cch/cch) and the deletion heterozygote (cch/C14cos) are unaffected (42)(43)(44)(45)(46). For example, the expression of glucose-6-phosphatase (42), tyrosine aminotransferase (Tat) and phosphoenolpyruvate carboxykinase (Pepck) -induction by glucocorticoids (44,45), and metallothionein (46) is2-to 4-fold decreased in the 14CoS/14CoS mouse, compared with the ch/ch and the ch/14CoS mouse, suggesting a gene on chromosome 7 that might encode one or more trans-acting positive regulatory factor(s).…”

Section: Radiation Deletion Mouse Linesmentioning

confidence: 99%

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Cellular Responses to Oxidative Stress: The [Ah] Gene Battery As a Paradigm

Nebert¹,

Petersen²,

Fornace³

1990

Environmental Health Perspectives

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A major source of oxidative stress in animals is plant stress metabolites, also termed phytoalexins. The aromatic hydrocarbon-responsive [Ah] gene battery is considered here as a model system in which we can study metabolically coordinated enzymes that respond to phytoalexin-induced oxidative stress. In the mouse, the [Ah] battery comprises at least six genes: two Phase I genes, CYPIAI and CYPIA2; and four Phase II genes, Nmo-1, Aldh-i, Ugt-1, and Gt-l. All six genes appear to be regulated positively by inducers such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other ligands of the Ah receptor. In the absence of foreign inducer, the control of Nmo-l gene expression is independent of the control of CYPIAI and CYPIA2 gene expression. The radiation deletion homozygote c 4Cot/C14Co5mouse is lacking about 1.1 centiMorgans of chromosome 7. Although having no detectable CYPIAI or CYPIA2 activation, the untreated C14CI/C14Cos mouse exhibits markedly elevated transcripts of the Nmo-i gene and three growth arrest-and DNA damage-inducible (gadd) genes. These data suggest that the missing region on chromosome 7 in the C14CoS/C14CoS mouse contains a gene(s), which we propose to call Nmo-In, encoding a trans-acting factor(s) that is a negative effector of the Nmo-l and gadd genes. The three other [Ah] battery Phase II genes behave similarly to Nmo-1 in the C14CoS/C14CoS mouse. This coordinated response to oxidative stress and DNA damage, by way of the release of a mammalian battery of genes from negative control, bears an interesting resemblance to the SOS response in bacteria.

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“…1990). These genes fail to respond to hormonal induction in the mutant liver (Schmid et al 1985;DeFranco et al 1988) despite the presence of the glucocorticoid receptor and components of the cAMP-signaling pathway ). On the basis of this phenotype, it was proposed that the lethal albino deletions remove a regulatory locus essential for the perinatal activation of hormone-responsive genes in liver (Gluecksohn-Waelsch 1987;GluecksohnWaelsch and DeFranco 1991).…”

mentioning

confidence: 99%

Rescue of mice homozygous for lethal albino deletions: implications for an animal model for the human liver disease tyrosinemia type 1.

Kelsey¹,

Ruppert²,

Beermann³

et al. 1993

Genes & Development

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Mice homozygous for specific deletions around the albino locus on chromosome 7 die within the first few hours of birth. They have a complex phenotype in liver and kidney, which includes multiple changes in gene expression and ultrastructural abnormalities. On the basis of this phenotype, it was proposed that these deletions remove a regulatory locus, all or hsdr-1. Recently, we and others showed that the gene for fumarylacetoacetate hydrolase (Fah), an enzyme involved in tyrosine catabolism, was disrupted by the lethal albino deletion c 14c°s. The finding that the Fah gene in wild-type mice is highly expressed only in cell types that develop a phenotype in mutants, and the fact that Fah deficiency determines the human liver disease hereditary tyrosinemia type 1 (HT1), suggested that disruption of the Fah gene was responsible for the lethal albino phenotype. To test this hypothesis, we have created lines of mice carrying Fah transgenes. We find that c 14c°s homozygotes which express transgenic Fah are complemented for all aspects of the complex lethal albino phenotype. Moreover, the degree to which the phenotype is corrected depends on the level of transgenic Fah expression. These results unequivocally establish Fah as the gene mapping at alf/hsdr-1 and prove that the phenotype depends ultimately on the blockage of tyrosine metabolism. Finally, they suggest lethal albino mice as an animal model for HT1.

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Metallothionein mRNA expression in mice homozygous for chromosomal deletions around the albino locus.

Cited by 26 publications

References 27 publications

The glucocorticoid hormone signal transduction pathway in mice homozygous for chromosomal deletions causing failure of cell type-specific inducible gene expression.

The glucocorticoid hormone signal transduction pathway in mice homozygous for chromosomal deletions causing failure of cell type-specific inducible gene expression.

Cellular Responses to Oxidative Stress: The [Ah] Gene Battery As a Paradigm

Rescue of mice homozygous for lethal albino deletions: implications for an animal model for the human liver disease tyrosinemia type 1.

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