Regulation, linkage, and sequence of mouse metallothionein I and II genes.

Searle, Peter F.; Davison, B L; Stuart, Gary W.; Wilkie, Thomas M.; Norstedt, Gunnar; Palmiter, Richard D.

doi:10.1128/mcb.4.7.1221

Cited by 336 publications

(174 citation statements)

References 37 publications

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“…Consensus GC boxes characteristic of Spl-binding sites are found for a number of cellular genes, such as hprt (48), aprt (15); 3-hydroxy-3-methylglutaryl coenzyme A reductase (56), c-myc (64,66), metallothioneins (57,62), thymidine kinase (39), 3-phosphoglycerate kinase (67), and adenosine deaminase (72). With (Fig.…”

Section: Discussionmentioning

confidence: 99%

Multiple transcription start sites, DNase I-hypersensitive sites, and an opposite-strand exon in the 5' region of the CHO dhfr gene.

Mitchell¹,

Carothers²,

Han³

et al. 1986

Mol. Cell. Biol.

164

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Transcription of the 26-kilobase (kb) dihydrofolate reductase (dhfr) gene in CHO cells is initiated at two sites: a major site (approximately 85% of the dhfr mRNA) at -63 relative to the translation start and a minor site (approximately 15%) at -107. Transcription also occwrs from the opposite DNA strand in the dhfr 5' region, with a probable initiation site at approximately -195 relative to the dhfr translation start. A 4-kb polyadenylated RNA that is derived from the opposite-strand transcription increases threefold in abundance after serum starvation of CHO cells for 24 h. dhfr mRNA levels do not change during this time. The first dhfr exon lies within a 1-kb genomic region marked by exceptionally high G+C content and lack of DNA methylation. This region also includes a 214.base-pair (bp) exon for the opposite-strand transcript and five of the six DNase I-hypersensitive sites identified at the dhfr locus. Gidoni, W. A. Dynan, and R. Tjian, Nature (London) 312: [409][410][411][412][413] 1984). Each of the three mammalian dhfr genes has several G-rich GC boxes proximal to the major dhfr transcription start site and several GC boxes of the opposite orientation (C rich) in a distal region about 500 bp upstream.The mammalian dihydrofolate reductase gene product (DHFR) is one of a group of S-phase-responsive enzymes important for DNA replication. Like other enzymes involved in DNA synthesis, DHFR activity is greater in proliferating cells than in quiescent cells (34). DHFR catalyzes the NADPH-dependent reduction of folate to dihydrofolate and then to tetrahydrofolate. Reduced folates are essential cofactors in the biosynthesis of glycine, purine nucleotides, and thymidylic acid. The de novo synthesis of the DNA precursor thymidylic acid during S phase is the major tetrahydrofolate-consuming reaction, and the cellular requirement for DHFR is highest at this time (34). However, even in rapidly proliferating cells, sufficient DHFR catalytic activity can be maintained by as few as 10 to 20 copies of mRNA per cell (32).Genes coding for low-abundance mRNAs represent the major portion of RNA polymerase II-specific genes that are expressed in any given cell type. Our understanding of the regulation of such genes is only just beginning. Some of the proteins encoded by low-copy mRNAs are tissue-specific enzymes and regulatory proteins involved in metabolic activities unique to a particular cellular phenotype. Others are proteins expressed to some extent in all cells and are commonly known as housekeeping gene products. The dihydrofolate reductase (dhfr) gene is referred to as a house-* Corresponding author. keeping gene because DHFR plays a role in several fundamental biosynthetic reactions, but the ternlinology is not meant to indicate that dhfr gene expression is uniform in all cells or at all times in a given cell. Housekeeping genes do show physiological and tissue-specific variations in expression. The development of cell lines with amplified dhfr genes has greatly facilitated the cloning and characterization of several...

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Section: Discussionmentioning

confidence: 99%

Multiple transcription start sites, DNase I-hypersensitive sites, and an opposite-strand exon in the 5' region of the CHO dhfr gene.

Mitchell¹,

Carothers²,

Han³

et al. 1986

Mol. Cell. Biol.

164

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“…Oligo(dT) (12)(13)(14)(15)(16)(17)(18) and RNAase H were purchased from Pharmacia-PL Biochemicals. ot-32P-deoxycytidine triphosphate (3000 Ci/mmole) was supplied by Amersham.…”

Section: Materials and Methods Materialsmentioning

confidence: 99%

An analysis of the rate of metallothionein mRNA POLY(A)-shortening using RNA blot hybridization

1985

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A progressive reduction in the size of rat metallothionein-l mRNA following induction by copper chloride or dexamethasone was demonstrated on RNA blots, and was shown to be due to shortening of the poly(A)-tail. The rate of poly(A) removal was the same in rat liver and kidney following copper chloride induction, in rat liver following dexamethasone induction, and in mouse liver following copper chloride induction. In mouse liver metallothionein-l and 2 mRNAs were shortened at the same rate.

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“…MT-I and -II exist in all tissues, are regulated in a coordinate fashion, and appear functionally equivalent (1)(2)(3). Other members of the MT gene family, however, show different patterns of expression: MT-III is found mainly in brain (4) and MT-IV in stratified squamous epithelium (5).…”

Section: Introductionmentioning

confidence: 99%

Induction of metallothionein as an adaptive mechanism affecting the magnitude and progression of toxicological injury.

Klaassen

Liu

1998

Environ Health Perspect

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Pretreatment of rats with low doses of Cd produces adaptive tolerance to a subsequent high dose of Cd-induced lethality, thus shifting the dose-response curve to the right. Cd pretreatment of animals also protects against the hepatotoxicity produced by high doses of Cd. This protection is attributable to the 10-to 50-fold induction of hepatic metallothionein (MT) by Cd pretreatment. As a result hepatic subcellular distribution of Cd is significantly altered, with more Cd bound to MT in the cytosol and a concomitant reduction of Cd in other critical organelles. In addition MTtransgenic animals are more resistant, whereas MT-null mice are more sensitive than controls to Cd-induced lethality and hepatotoxicity. This further demonstrates that MT is important in Cd detoxication. Induction of hepatic MT by zinc also protects mice from carbon tetrachloride (CCI4)-induced liver injury, with more 14C-CCI4 bound to MT in the cytosol. MT-null mice are more sensitive to CCI4-induced hepatotoxicity, which supports the hypothesis that induction of MT also plays a protective role for nonmetallic chemicals. These results indicate that MT is a part of cellular adaptive mechanisms affecting the magnitude and progression of toxic insults from metals such as Cd as well as from organic chemicals such as CCI4. -Environ Health Perspect 1 06(Suppl 1):297-300 (1998). http.//ehpnetl.niehs.nih.gov/docs/1998/Suppl-1/297-300klaassen/ abstract.html

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Regulation, linkage, and sequence of mouse metallothionein I and II genes.

Cited by 336 publications

References 37 publications

Multiple transcription start sites, DNase I-hypersensitive sites, and an opposite-strand exon in the 5' region of the CHO dhfr gene.

Multiple transcription start sites, DNase I-hypersensitive sites, and an opposite-strand exon in the 5' region of the CHO dhfr gene.

An analysis of the rate of metallothionein mRNA POLY(A)-shortening using RNA blot hybridization

Induction of metallothionein as an adaptive mechanism affecting the magnitude and progression of toxicological injury.

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