Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Catfish hepatic metallothionein was purified to homogeneity by Sephadex G-75 gel filtration, DEAE-Sephadex A-25 column chromatography and preparative polyacrylamide gel electrophoresis. Induction by cadmium and zinc, characteristic UV spectrum, cadmium binding property and its low MW established that it was a metallothionein. Antibody was raised in rabbit against catfish metallothionein. Catfish antimetallothionein cross-reacted with other fish metallothioneins but not with chicken or rodent metallothionein. Catfish metallothionein is more electronegative as compared to mouse, rat, chicken or hamster metallothionein. Catfish MT appeared to aggregate readily on storage and to be less electronegative.
Mol Cell Biochem 1987 Nov
PMID:Purification and immunological characterization of catfish (Heteropneustes fossilis) metallothionein. 345 69

Using the technique of genomic footprinting, we demonstrate cadmium-inducible protection from dimethyl sulfate (DMS) modification of guanine residues in vivo in five metal-responsive elements (MREs) in the promoter of the rat metallothionein 1 (MT-1) gene. We also identify a site of extreme DMS hyperreactivity which, like the MRE protection, occurs only after metal ion induction. With this hyperreactive site as an indicator, we can measure the kinetics of induction and deinduction. Changes in the intracellular metal ion concentrations are reflected in alterations in the reactivity with DMS of guanine residues in the MT-1 gene promoter. Lastly, for both control and metal-induced cells, we observe DMS protection and enhancement of a binding site (located 5' of the distal MRE) which is a consensus sequence for the Sp1 transcription factor. Transfection experiments with deletion mutations of a fusion gene construct indicate both that a sequence region which includes this GC box regulates the basal level of expression of the MT-1 gene and that increasing the number of MREs in the promoter increases the induced level of transcription. Our genomic footprinting and transfection data together suggest that (i) a transcription factor, possibly Sp1, plays an important role in regulating the basal level of expression of the MT-1 gene and (ii) metal induction involves the metal-dependent binding to a sequence-specific binding factor which responds to changes in intracellular metal ion levels.
Mol Cell Biol 1987 Oct
PMID:Metal-dependent binding of a factor in vivo to the metal-responsive elements of the metallothionein 1 gene promoter. 368 94

We examined the chromatin structure of the rat metallothionein I gene, both in uninduced cells and in cells induced by heavy metals or dexamethasone, using hypersensitivity to DNase I as an assay. The metallothionein I gene of the H4IIE rat hepatoma cell line, expressed at basal level, has a single DNase I-hypersensitive site. This site maps between putative hormone and basal level control sequences. Induction of the gene by cadmium or zinc resulted in the appearance of a new hypersensitive site near the start site of transcription, in a region near the metal-regulatory elements. In contrast, induction of the metallothionein I gene by dexamethasone did not alter the basal pattern of hypersensitivity. Thus, different mechanisms of induction of metallothionein transcription lead to distinct alterations in the chromatin containing the 5' sequences regulating the expression of this gene.
Mol Cell Biol 1986 Jul
PMID:Alternative inducers of the rat metallothionein I gene cause distinct changes in chromatin structure in the 5' region of the gene. 378 3

The effect of high K+/low Na+-Tyrode's solution on Ca2+ uptake into neonatal rat atrium was studied using 45Ca2+. Substitution of 60-129 mM Na+ in Tyrode's solution by equimolar concentrations of K+ or choline, significantly (with the exception of 60 mM choline substitution) increased Ca2+ uptake above control. Furthermore, the Ca2+ uptake stimulated by K+ substitution was significantly greater than that stimulated by choline substitution at the corresponding concentrations. The choline/low Na+-induced Ca2+ uptake (i.e. that above the Ca2+ uptake measured in normal Tyrode's solution) was increased by pre-exposure to either ice-cold Tyrode's solution for 1 h (approximately 36% increase) or to K+-free Tyrode's solution for 3 h (approximately 100% increase). The choline/low Na+-induced Ca2+ uptake was abolished by the hypertonic addition of NaCl (returning the bathing Na+ concentration to normal), increased (approximately 140%) by the addition of 1.8 mM PO4(3-)-free Hepes buffered choline/low Na+ media, but unaffected by 0.2 mM cadmium. The high K+/low Na+-induced Ca2+ uptake (i.e. that above the Ca2+ uptake measured in normal Tyrode's solution) was relatively insensitive to pre-exposure to cold (0% change) or K+-free media (11% increase) and only 50% inhibited by the hypertonic addition of NaCl (returning the bathing Na+ concentration to normal). However, the high K+/low Na+-induced Ca2+ uptake was 57% inhibited by 0.2 mM cadmium and approximately 30% inhibited by the addition of 1.8 mM PO4(3-) to HCO3-/PO4(3-)-free Hepes buffered high K+/low Na+ media.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1986 Nov
PMID:Ca2+ transport systems mediating the high K+/low Na+-induced uptake of Ca2+ into rat atrium. 379 76

Alpha interferon treatment of CHO cells elicits the rapid synthesis of many gene products, including metallothionein (MT), a protein which avidly binds heavy metals such as zinc, cadmium, and copper. Since MTs appear to have a pleiotropic role in the cell, ranging from metal detoxification to free-radical scavenging, interferon treatment may trigger a generalized defense mechanism. Activation by interferon, however, was transient, with MT mRNA being maximally detectable by a cytodot procedure within the first hour. Subsequent addition of interferon was ineffective until 7 h after the initial treatment. The action of zinc, a potent inducer of MT, however, remained independent of alpha interferon induction. The transient nature of induction by interferon was examined for altered rate of MT mRNA turnover.
Mol Cell Biol 1987 Feb
PMID:Transient response of amplified metallothionein genes in CHO cells to induction by alpha interferon. 382 25

The human metallothionein IIA (hMT-IIA) gene contains two enhancer elements whose activity is induced by heavy-metal ions such as Cd2+. To determine the nature of the relationship between the metal-responsive elements and the element(s) responsible for the basal activity of the enhancers, the basal-level enhancer element(s), the hMT-IIA enhancers were subjected to mutational analysis. We show that deletion of the metal-responsive elements had no effect on the basal activity of the enhancer but prevented further induction by Cd2+. On the other hand, replacement of the basal-level enhancer element with linker DNA led to inactivation of the enhancer both before and after treatment with Cd2+. Therefore, the metal-responsive elements seems to act as a positive modulator of enhancer function in the presence of heavy-metal ions. In addition to the two enhancers, the hMT-IIA promoter contained one other element, the GC box, required for its basal expression. Unlike deletion of the basal-level enhancer element, replacement of the GC box with linker DNA had no effect on the ability of the promoter to be induced by Cd2+.
Mol Cell Biol 1987 Feb
PMID:Metal-responsive elements act as positive modulators of human metallothionein-IIA enhancer activity. 382 26

Recombinant DNA probes complementary to Chinese hamster metallothionein (MT)-1 and MT-2 mRNAs were used to compare MT gene copy numbers, zinc-induced MT mRNA levels, and uninduced MT mRNA levels in cadmium-resistant (Cdr) Chinese hamster ovary cell lines. Quantitative hybridization analyses determined that the MT-1 and MT-2 genes are each present at approximately single-copy levels in the genome of cell line Cdr2C10 and are coordinately amplified approximately 7, 3, and 12 times over the Cdr2C10 value in the genomes of cell lines Cdr20F4, Cdr30F9, and Cdr200T1, respectively. The maximum zinc-induced MT-1 mRNA concentrations in cell lines Cdr20F4, Cdr30F9, and Cdr200T1 were equal to 1, 3, and 15 times that measured in Cdr2C10, respectively. Similarly, the maximum zinc-induced MT-2 mRNA concentrations were equal to 1, 3, and 14 times that measured in Cdr2C10, respectively, and in each instance they were 90 to 150 times greater than their respective concentrations in uninduced cells. Thus, relative MT gene numbers are closely correlated with both zinc-induced and uninduced MT mRNA levels in Cdr2C10, Cdr30F9, and Cdr200T1, but not in Cdr20F4. Each of the latter two lines possesses structurally altered chromosomes whose breakpoints are near the MT locus. Nonetheless, the ratio of the levels of MT-1 to MT-2 mRNAs was constant in each of the four cell lines, including Cdr20F4. These results demonstrate that MT-1 and MT-2 mRNAs are induced coordinately in each Cdr cell line. Therefore, the coordination of the induction of MT-1 and MT-2 mRNA is independent of MT gene amplification, MT gene rearrangement, and the relative inducibilities of amplified MT genes. However, MT mRNA and protein levels each indicate that MT-1 and MT-2 expression is non-coordinate in uninduced cells. Thus, regulation of MT expression may involve two different mechanisms which are differentially operative in induced and uninduced cells.
Mol Cell Biol 1985 Dec
PMID:Coordinate expression of amplified metallothionein I and II genes in cadmium-resistant Chinese hamster cells. 383 47

Regulation of the endogenous mouse metallothionein I and II (MT-I and MT-II) genes by heavy metals and glucocorticoids was studied in cultured mouse cells. Both mRNAs were measured simultaneously by solution hybridization with [3H]MT-I cDNA and [32P]MT-II cDNA, and the absolute amount of each mRNA was calculated by using a single-stranded M13 standard that contained both mRNA sequences. Both genes responded identically to different concentrations of metals (zinc, cadmium, and copper) and dexamethasone. Furthermore, the time courses of induction of both mRNAs were the same. However, under all conditions there was 1.2- to 1.9-fold more MT-I mRNA than MT-II mRNA. We conclude that both genes are regulated identically by receptors for glucocorticoids and metals but that the rate of transcription from the MT-I gene is slightly higher than from the MT-II gene.
Mol Cell Biol 1985 Feb
PMID:Coordinate regulation of mouse metallothionein I and II genes by heavy metals and glucocorticoids. 383 60

Golden hamster, mouse and rat hepatic cadmium metallothioneins (MT) were purified by Sephadex G-75 gel filtration, DEAE-Sephadex A-25 chromatography and activated Thiol-Sepharose 4B affinity chromatography. Metallothioneins were separated by DEAE-Sephadex A-25 chromatography into two forms: MT-1 and MT-2. In mouse and golden hamster liver, MT-1 was the major form. The purified proteins were homogeneous as judged by polyacrylamide gel electrophoresis in the presence and absence of sodium dodecyl sulfate. In non-denaturing polyacrylamide gel electrophoresis, migration of mouse, rat and golden hamster hepatic metallothioneins were found to be different. Antibodies to mouse hepatic MT-1 was raised in rabbits. The antiserum cross reacted with mouse and hamster MT-1 and MT-2 giving a single precipitin band. Mouse, rat and hamster hepatic MTs are immunologically identical but electrophoretically different. The kidney and pancreatic MTs of rat and golden hamster were purified by Sephadex G-75 gel filtration. They were immunologically distinct. Pancreas MT formed a line of partial identity with hepatic MTs. Kidney MTs form two precipitin band one identical with the pancreatic form and another of complete identity with the hepatic MTs. This indicates the presence of tissue specific MTs.
Mol Cell Biochem 1985 Sep
PMID:Immunological and biochemical properties of metallothioneins of golden hamster, mouse and rat. 393 42

Barsoum and Varshavsky (Proc. Natl. Acad. Sci. U.S.A. 80:5330-5334, 1983) suggest that polypeptide mitogens and the mitogenic tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulate gene amplification by related pathways. I demonstrated that TPA and the polypeptide mitogen fibroblast growth factor (FGF) both increase the frequency of cadmium-resistant variants of Swiss-Webster 3T3 cells. The molecular basis for this phenomenon is the amplification of the metallothionein gene(s). To further characterize the relationship between mitogenesis and gene amplification, I examined the ability of TPA and FGF to increase the frequency of cadmium-resistant colonies in the 3T3 variant cell line 3T3-TNR9. Unlike 3T3 cells, 3T3-TNR9 cells cannot be stimulated by TPA to divide (E. Butler-Gralla and H. R. Herschman, J. Cell. Physiol. 107:59-68, 1981). TPA does not induce an increase in cadmium-resistant colonies of the TPA-nonproliferative 3T3-TNR9, variant, in contrast to its efficacy on 3T3 cells. FGF, a potent mitogen for 3T3-TNR9 cells as well as 3T3 cells, is equally effective for 3T3-TNR9 and 3T3 cells in inducing cadmium-resistant colonies. These data suggest that the pathways of TPA-induced gene amplification and TPA-stimulated mitogenesis share a common step(s). TPA caused transient inhibition of DNA synthesis in both dividing 3T3 and 3T3-TNR9 cells, suggesting that this latter response to TPA is not sufficient to enhance gene amplification.
Mol Cell Biol 1985 May
PMID:A 12-O-tetradecanoylphorbol-13-acetate (TPA)-nonproliferative variant of 3T3 cells is resistant to TPA-enhanced gene amplification. 400 Jan 20


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