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. 1986 May;83(10):3346–3350. doi: 10.1073/pnas.83.10.3346

Cell specificity and an effect of ras on human metallothionein gene expression.

C J Schmidt, D H Hamer
PMCID: PMC323510  PMID: 3517857

Abstract

The expression of three human metallothionein (hMT) genes has been compared in various established cell lines and primary liver. The single gene for hMT isoform II is ubiquitously expressed in all cell types in response to cadmium. In contrast, two genes encoding hMT-I isoforms are expressed in a highly specific, reciprocal fashion that correlates with the embryonic germ layer origin of the cells. In one cell line that failed to express detectable amounts of hMT-IE, treatment with the demethylating agent 5-azacytidine led to cadmium-inducible expression of this subtype. The genes for both MT-I isoforms are coordinately inducible by heavy metals but differ in their response to glucocorticoids. Surprisingly, cells transformed with the Ha-ras oncogene contain elevated basal levels of both MT-I and MT-II RNA. The implications of these results for growth-related and developmental functions of MT are discussed.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andersen R. D., Piletz J. E., Birren B. W., Herschman H. R. Levels of metallothionein messenger RNA in foetal, neonatal and maternal rat liver. Eur J Biochem. 1983 Apr 5;131(3):497–500. doi: 10.1111/j.1432-1033.1983.tb07289.x. [DOI] [PubMed] [Google Scholar]
  2. Andrews P. W. Retinoic acid induces neuronal differentiation of a cloned human embryonal carcinoma cell line in vitro. Dev Biol. 1984 Jun;103(2):285–293. doi: 10.1016/0012-1606(84)90316-6. [DOI] [PubMed] [Google Scholar]
  3. Beach L. R., Palmiter R. D. Amplification of the metallothionein-I gene in cadmium-resistant mouse cells. Proc Natl Acad Sci U S A. 1981 Apr;78(4):2110–2114. doi: 10.1073/pnas.78.4.2110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bubeník J., Perlmann P., Helmstein K., Moberger G. Cellular and humoral immune responses to human urinary bladder carcinomas. Int J Cancer. 1970 May 15;5(3):310–319. doi: 10.1002/ijc.2910050303. [DOI] [PubMed] [Google Scholar]
  5. Carter A. D., Felber B. K., Walling M. J., Jubier M. F., Schmidt C. J., Hamer D. H. Duplicated heavy metal control sequences of the mouse metallothionein-I gene. Proc Natl Acad Sci U S A. 1984 Dec;81(23):7392–7396. doi: 10.1073/pnas.81.23.7392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Compere S. J., Palmiter R. D. DNA methylation controls the inducibility of the mouse metallothionein-I gene lymphoid cells. Cell. 1981 Jul;25(1):233–240. doi: 10.1016/0092-8674(81)90248-8. [DOI] [PubMed] [Google Scholar]
  7. Durnam D. M., Hoffman J. S., Quaife C. J., Benditt E. P., Chen H. Y., Brinster R. L., Palmiter R. D. Induction of mouse metallothionein-I mRNA by bacterial endotoxin is independent of metals and glucocorticoid hormones. Proc Natl Acad Sci U S A. 1984 Feb;81(4):1053–1056. doi: 10.1073/pnas.81.4.1053. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Durnam D. M., Palmiter R. D. Induction of metallothionein-I mRNA in cultured cells by heavy metals and iodoacetate: evidence for gratuitous inducers. Mol Cell Biol. 1984 Mar;4(3):484–491. doi: 10.1128/mcb.4.3.484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fogh J., Wright W. C., Loveless J. D. Absence of HeLa cell contamination in 169 cell lines derived from human tumors. J Natl Cancer Inst. 1977 Feb;58(2):209–214. doi: 10.1093/jnci/58.2.209. [DOI] [PubMed] [Google Scholar]
  10. Friedman R. L., Manly S. P., McMahon M., Kerr I. M., Stark G. R. Transcriptional and posttranscriptional regulation of interferon-induced gene expression in human cells. Cell. 1984 Oct;38(3):745–755. doi: 10.1016/0092-8674(84)90270-8. [DOI] [PubMed] [Google Scholar]
  11. Friedman R. L., Stark G. R. alpha-Interferon-induced transcription of HLA and metallothionein genes containing homologous upstream sequences. Nature. 1985 Apr 18;314(6012):637–639. doi: 10.1038/314637a0. [DOI] [PubMed] [Google Scholar]
  12. Graham F. L., Smiley J., Russell W. C., Nairn R. Characteristics of a human cell line transformed by DNA from human adenovirus type 5. J Gen Virol. 1977 Jul;36(1):59–74. doi: 10.1099/0022-1317-36-1-59. [DOI] [PubMed] [Google Scholar]
  13. Hackett A. J., Smith H. S., Springer E. L., Owens R. B., Nelson-Rees W. A., Riggs J. L., Gardner M. B. Two syngeneic cell lines from human breast tissue: the aneuploid mammary epithelial (Hs578T) and the diploid myoepithelial (Hs578Bst) cell lines. J Natl Cancer Inst. 1977 Jun;58(6):1795–1806. doi: 10.1093/jnci/58.6.1795. [DOI] [PubMed] [Google Scholar]
  14. Karin M., Eddy R. L., Henry W. M., Haley L. L., Byers M. G., Shows T. B. Human metallothionein genes are clustered on chromosome 16. Proc Natl Acad Sci U S A. 1984 Sep;81(17):5494–5498. doi: 10.1073/pnas.81.17.5494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Karin M., Haslinger A., Holtgreve H., Cathala G., Slater E., Baxter J. D. Activation of a heterologous promoter in response to dexamethasone and cadmium by metallothionein gene 5'-flanking DNA. Cell. 1984 Feb;36(2):371–379. doi: 10.1016/0092-8674(84)90230-7. [DOI] [PubMed] [Google Scholar]
  16. Karin M., Haslinger A., Holtgreve H., Richards R. I., Krauter P., Westphal H. M., Beato M. Characterization of DNA sequences through which cadmium and glucocorticoid hormones induce human metallothionein-IIA gene. Nature. 1984 Apr 5;308(5959):513–519. doi: 10.1038/308513a0. [DOI] [PubMed] [Google Scholar]
  17. Karin M., Richards R. I. Human metallothionein genes--primary structure of the metallothionein-II gene and a related processed gene. Nature. 1982 Oct 28;299(5886):797–802. doi: 10.1038/299797a0. [DOI] [PubMed] [Google Scholar]
  18. Knowles B. B., Howe C. C., Aden D. P. Human hepatocellular carcinoma cell lines secrete the major plasma proteins and hepatitis B surface antigen. Science. 1980 Jul 25;209(4455):497–499. doi: 10.1126/science.6248960. [DOI] [PubMed] [Google Scholar]
  19. Kraus M. H., Yuasa Y., Aaronson S. A. A position 12-activated H-ras oncogene in all HS578T mammary carcinosarcoma cells but not normal mammary cells of the same patient. Proc Natl Acad Sci U S A. 1984 Sep;81(17):5384–5388. doi: 10.1073/pnas.81.17.5384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kägi J. H., Vasák M., Lerch K., Gilg D. E., Hunziker P., Bernhard W. R., Good M. Structure of mammalian metallothionein. Environ Health Perspect. 1984 Mar;54:93–103. doi: 10.1289/ehp.54-1568188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Leibovitz A., Stinson J. C., McCombs W. B., 3rd, McCoy C. E., Mazur K. C., Mabry N. D. Classification of human colorectal adenocarcinoma cell lines. Cancer Res. 1976 Dec;36(12):4562–4569. [PubMed] [Google Scholar]
  22. Leone A., Pavlakis G. N., Hamer D. H. Menkes' disease: abnormal metallothionein gene regulation in response to copper. Cell. 1985 Feb;40(2):301–309. doi: 10.1016/0092-8674(85)90144-8. [DOI] [PubMed] [Google Scholar]
  23. Mayo K. E., Palmiter R. D. Glucocorticoid regulation of metallothionein-I mRNA synthesis in cultured mouse cells. J Biol Chem. 1981 Mar 25;256(6):2621–2624. [PubMed] [Google Scholar]
  24. McAllister R. M., Gardner M. B., Greene A. E., Bradt C., Nichols W. W., Landing B. H. Cultivation in vitro of cells derived from a human osteosarcoma. Cancer. 1971 Feb;27(2):397–402. doi: 10.1002/1097-0142(197102)27:2<397::aid-cncr2820270224>3.0.co;2-x. [DOI] [PubMed] [Google Scholar]
  25. PISCATOR M. OM KADMIUM I NORMALA MAENNISKONJURAR SAMT REDOGOERELSE FOER ISOLERING AV METALLOTHIONEIN UR LEVER FRAN KADMIUMEXPONERADE KANINER. Nord Hyg Tidskr. 1964;45:76–82. [PubMed] [Google Scholar]
  26. Popovic M., Sarngadharan M. G., Read E., Gallo R. C. Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science. 1984 May 4;224(4648):497–500. doi: 10.1126/science.6200935. [DOI] [PubMed] [Google Scholar]
  27. Reddy E. P., Reynolds R. K., Santos E., Barbacid M. A point mutation is responsible for the acquisition of transforming properties by the T24 human bladder carcinoma oncogene. Nature. 1982 Nov 11;300(5888):149–152. doi: 10.1038/300149a0. [DOI] [PubMed] [Google Scholar]
  28. Richards R. I., Heguy A., Karin M. Structural and functional analysis of the human metallothionein-IA gene: differential induction by metal ions and glucocorticoids. Cell. 1984 May;37(1):263–272. doi: 10.1016/0092-8674(84)90322-2. [DOI] [PubMed] [Google Scholar]
  29. Rugstad H. E., Norseth T. Cadmium resistance and content of cadmium-binding protein in two enzyme-deficient mutants of mouse fibroblasts (L-cells). Biochem Pharmacol. 1978 Mar 1;27(5):647–650. doi: 10.1016/0006-2952(78)90499-9. [DOI] [PubMed] [Google Scholar]
  30. Rugstad N. E., Norseth T. Cadmium resistance and content of cadmium-binding protein in cultured human cells. Nature. 1975 Sep 11;257(5522):136–137. doi: 10.1038/257136a0. [DOI] [PubMed] [Google Scholar]
  31. Schmidt C. J., Hamer D. H., McBride O. W. Chromosomal location of human metallothionein genes: implications for Menkes' disease. Science. 1984 Jun 8;224(4653):1104–1106. doi: 10.1126/science.6719135. [DOI] [PubMed] [Google Scholar]
  32. Schmidt C. J., Jubier M. F., Hamer D. H. Structure and expression of two human metallothionein-I isoform genes and a related pseudogene. J Biol Chem. 1985 Jun 25;260(12):7731–7737. [PubMed] [Google Scholar]
  33. Searle P. F., Davison B. L., Stuart G. W., Wilkie T. M., Norstedt G., Palmiter R. D. Regulation, linkage, and sequence of mouse metallothionein I and II genes. Mol Cell Biol. 1984 Jul;4(7):1221–1230. doi: 10.1128/mcb.4.7.1221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Seiler-Tuyns A., Birnstiel M. L. Structure and expression in L-cells of a cloned H4 histone gene of the mouse. J Mol Biol. 1981 Oct 5;151(4):607–625. doi: 10.1016/0022-2836(81)90426-5. [DOI] [PubMed] [Google Scholar]
  35. Tabin C. J., Bradley S. M., Bargmann C. I., Weinberg R. A., Papageorge A. G., Scolnick E. M., Dhar R., Lowy D. R., Chang E. H. Mechanism of activation of a human oncogene. Nature. 1982 Nov 11;300(5888):143–149. doi: 10.1038/300143a0. [DOI] [PubMed] [Google Scholar]
  36. Yaswen P., Goyette M., Shank P. R., Fausto N. Expression of c-Ki-ras, c-Ha-ras, and c-myc in specific cell types during hepatocarcinogenesis. Mol Cell Biol. 1985 Apr;5(4):780–786. doi: 10.1128/mcb.5.4.780. [DOI] [PMC free article] [PubMed] [Google Scholar]

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