Turnover of metallothioneins in rat liver

Andersen, Robert D.; Winter, William P.; Maher, Jacquelyn J.; Bernstein, Isadore A.

doi:10.1042/bj1740327

Cited by 72 publications

(27 citation statements)

References 30 publications

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“…The present assay, based on testing such changes in metallothionein, is more sensitive than the one with cytochrome b 5 described previously (Jauch and Lutz, 1983) because of the following advantages: Firstly, the rate of MT synthesis can be stimulated by administration of metal ions, particularly cadmium. The induced rate of synthesis can reach values of 2-3 nmoles/h/g liver (Andersen et al, 1978), i.e., 20-30 times higher than the rate of cytochrome b 5 synthesis and at least 10 times higher than for the average cytosolic liver protein. It should be mentioned here that it is not the total amount of a specific protein chain in the cell which is important for the Iimit of detection of variants in this type of assay but the rate of synthesis during that time period when the radiolabelled "wrong" amino acids are available for incorporation.…”

Section: Discussionmentioning

confidence: 89%

“…3 control rats received water in the place of both subchronic and acute carcinogen treatments. At 10.00 hall animals were given a subcutaneous injection of CdC1 2 in 10-4 M HCI (1 mg Cd/rat) in the scapular region in order to induce MT synthesis (Andersen et al, 1978). At 14.00 h a liquid synthetic diet was given by gavage (7.2 ml/kg) which contained 16% sucrose plus about one third of the daily requirement of all amino acids except the aromatic amino acids tyrosine and phenylalanine.…”

Section: Animamentioning

confidence: 99%

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Metallothionein protein variants generated in rat liver as a result of DNA and RNA ethylations by the carcinogen diethylnitrosamine

Jauch

Lutz

1986

Mutation Research/Environmental Mutagenesis and Related Subject

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SummaryMetallothionein (MT) is a protein which contains 20 cysteine residues but no aromatic amino acids. It was tested whether treatment of male rats with the hepatocarcinogen diethylnitrosamine (DENA) could ethylate nucleic acids in such a way that protein variants containing measurable amounts of aromatic amino acid residues could be isolated from the livers of treated animals. To give a low Iimit of detection, the "wrong" amino acid precursors were administered in radiolabelled form at high Ievels of activity (7 mCijkg each of [ 3 H]tyrosine and [ 3 H]phenylalanine). 11 p.Cijkg [ 14 C]cysteine was given as an intemal marker for MT biosynthesis. 6 h after amino acid administration, metallothionein (MT) was isolated from the liver and extensively purified. Afteracid hydrolysis and collection of Cys, Tyr, and Phe from an HPLC analysis of the amino acids, the 3 Hj 14 C ratio was determined. The carcinogen-treated rats exhibited a significantly higher ratio than the vehicle-treated animals. This type of in vivo assay might find interesting applications in the investigation of nucleic acid alkylations as promutagenic lesions.Since a !arge number of chemical carcinogens act by damaging DNA, many short-term screening tests for carcinogenicity are based upon the detection of mutational events. In the light of the recent findings that certain cellular proto-oncogenes can be activated by base Substitutions (refs. in Weinberg, 1985) the search for changes in amino acid composition of proteins could become a valuable tool.One majorproblern in proteinvariant analysis in non-clonal systems is the fact that minor changes in the relative abundance of the various amino acids in a small number of polypeptide * Present address:

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Section: Discussionmentioning

confidence: 89%

Section: Animamentioning

confidence: 99%

Metallothionein protein variants generated in rat liver as a result of DNA and RNA ethylations by the carcinogen diethylnitrosamine

Jauch

Lutz

1986

Mutation Research/Environmental Mutagenesis and Related Subject

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“…The exposure of these cells to cadmium may simply lead to the binding of metal to pre-existent protein, not to the induction of new binding protein, as occurs when rat liver encounters cadmium ion (Andersen et al, 1978;Richards & Cousins, 1975 , although the 33% decrease in zinc content of tumour cells in Zn(-) animals was not observed earlier. There is no marked, repeatable difference in the profile of the zinc in cell cytosol or particulate fraction between Zn(+) or Zn(-) tumours ( Fig.…”

Section: Discussionmentioning

confidence: 93%

Zinc-, copper- and cadmium-binding protein in Ehrlich ascites tumour cells

Koch¹,

Wielgus²,

Shankara³

et al. 1980

Biochemical Journal

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The properties of Ehrlich ascites tumour cells exposed in vivo to cadmium were investigated as a function of the zinc status of the host animals. Tumour-cell growth was inhibited by cadmium in both zinc-sufficient and zinc-deficient animals. However, cells in zinc-sufficient tumours accumulate much less cadmium than those in deficient tumours. The subcellular distributions of cadmium and zinc do not depend on zinc status. Cadmium and zinc are bound to a low-molecular-weight protein with properties similar to metallothionein. Without exposure to cadmium, a zinc-and copper-binding protein is still present that behaves like a metallothionein. This protein can rapidly bind cadmium added to Ehrlich cells in vitro. It is shown that the zinc-and copper-binding protein contains free thiol groups. Ehrlich cells isolated from cadmium-treated animals are viable and show normal incorporation of uridine into RNA, but the cellular uptake of thymidine and its incorporation into DNA are inhibited.

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“…Metallothioneins are usually isolated as two major isoforms, designated MT-1 and MT-2. The metallothionein (MT) genes are inducible by metal ions (4,17), glucocorticoid hormones (19,20,36,37), stress (51), bacterial endotoxin (16), iodoacetate (18), and interferon (22). Human MT-1 and MT-2 genes show differential expression with metal ion and hormone inducers (57).…”

mentioning

confidence: 99%

Rat metallothionein-1 structural gene and three pseudogenes, one of which contains 5'-regulatory sequences.

Andersen¹,

Birren²,

Taplitz³

et al. 1986

Mol. Cell. Biol.

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As shown by Southern blot analysis, the metallothionein-1 (MT-1) genes in rats comprise a multigene family. We present the sequence of the MT-1 structural gene and compare its features with other metaliothionein genes. Three MT-1 pseudogenes which we sequenced apparently arose by reverse transcription of processed mRNA transcripts. Two of these, MT-1*a and MT-l*c, are retrogenes which derive from the MT-1 mRNA, having diverged from the MT-1 gene 6.9 and 2.6 million years ago, respectively. The third, MT-l*b, differs from the MT-1 cDNA by only three nucleotide alterations. Surprisingly, MT-l*b also preserves sequence homology for 142 base pairs 5' to the transcription initiation site of the parent gene; it contains a promoter sequence sufficient for specifying metal ion induction. We identified, by Si nuclease mapping, an RNA polymerase II initiation site 432 base pairs 5' of the MT-1 transcription initiation site of the MT-1 structural gene which could explain the formation of the mRNA precursor to this pseudogene. We were unable to detect MT-i*b transcripts, either in liver tissue or after transfection. We conclude that the absence of detectable transcripts from this pseudogene is due to either a reduced level of transcription or the formation of unstable transcripts as a consequence of the lack of a consensus sequence normally found 3' of transcription termination in the MT-1 structural gene.Metallothioneins are 6,000-dalton, cysteine-rich proteins that bind the metal ions zinc, copper, cadmium, and mercury (see 32 for review). Metallothioneins are usually isolated as two major isoforms, designated MT-1 and MT-2. The metallothionein (MT) genes are inducible by metal ions (4, 17), glucocorticoid hormones (19,20,36,37), stress (51), bacterial endotoxin (16), iodoacetate (18), and interferon (22). Human MT-1 and MT-2 genes show differential expression with metal ion and hormone inducers (57). The proposed functional roles of metallothioneins include: protection against heavy metal ion intoxication by cadmium or mercury (49); biological response to stress (51,64), and regulation of zinc and copper during development (3,5,52,59). The existence of numerous independent induction responses to different agents regulating MT gene expression suggests a complex role for the regulatory recognition sequences in these genes (16,22,30,43). The sequencing of members of a family of MT genes allowed us both to explore in detail the evolutionary relationship among these genes and to compare the regions of sequence involved in regulating MT gene expression. MATERIALS AND METHODSScreening of Charon 4a library, DNA sequence analysis, and computer analysis of sequence data. The screening of a rat liver Charon 4a genomic library for MT-1 sequences and the restriction maps for the inserts in p34 (MT-1 structural gene), p21 (MT-ltja), p27 (MT-lhb), and p5 (MT-14c) have already been reported (2). The sequence analysis of these clones was done by a combination of base-specific chemical cleavage of 5' end-labeled restriction fragments from...

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Turnover of metallothioneins in rat liver

Cited by 72 publications

References 30 publications

Metallothionein protein variants generated in rat liver as a result of DNA and RNA ethylations by the carcinogen diethylnitrosamine

Metallothionein protein variants generated in rat liver as a result of DNA and RNA ethylations by the carcinogen diethylnitrosamine

Zinc-, copper- and cadmium-binding protein in Ehrlich ascites tumour cells

Rat metallothionein-1 structural gene and three pseudogenes, one of which contains 5'-regulatory sequences.

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