Metallothionein-human GH fusion genes stimulate growth of mice.

The promoter or regulatory region of the mouse gene for metallothionein-I was fused to the structural gene coding for human growth hormone. These fusion genes were introduced into mice by microinjection of fertilized eggs. Twenty-three (70 percent) of the mice that stably incorporated the fusion genes showed high concentrations of human growth hormone in their serum and grew significantly larger than control mice. Synthesis of human growth hormone was induced further by cadmium or zinc, which normally induce metallothionein gene expression. Transgenic mice that expressed human growth hormone also showed increased concentrations of insulin-like growth factor I in their serum. Histology of their pituitaries suggests dysfunction of the cells that normally synthesize growth hormone. The fusion genes were expressed in all tissues examined, but the ratio of human growth hormone messenger RNA to endogenous metallothionein-I messenger RNA varied among different tissues and different animals, suggesting that expression of the foreign genes is influenced by site of integration and tissue environment.

[1]  J. Hirsh,et al.  The cloned dopa decarboxylase gene is developmentally regulated when reintegrated into the drosophila genome , 1983, Cell.

[2]  M. Preece,et al.  Effects of growth hormone, prolactin and thyroxine on body wegith, somatomedin-like activity and in-vivo sulphation of cartilage in hypopituitary dwarf mice. , 1980, The Journal of endocrinology.

[3]  A. Herington,et al.  Hepatic binding of human and bovine growth hormones and ovine prolactin in the dwarf "little" mouse. , 1983, Endocrinology.

[4]  E. Schoenle,et al.  Insulin-like growth factor I stimulates growth in hypophysectomized rats , 1982, Nature.

[5]  S. Handwerger,et al.  Developmental patterns of insulin-like growth factor-I and -II synthesis and regulation in rat fibroblasts , 1983, Nature.

[6]  R. Palmiter,et al.  Differential regulation of metallothionein-thymidine kinase fusion genes in transgenic mice and their offspring , 1982, Cell.

[7]  N. Ling,et al.  Hypothalamic Polypeptide That Inhibits the Secretion of Immunoreactive Pituitary Growth Hormone , 1973, Science.

[8]  P. Seeburg,et al.  Nucleotide sequence of part of the gene for human chorionic somatomammotropin: Purification of DNA complementary to predominant mRNA species , 1977, Cell.

[9]  E. Eicher,et al.  Stimulation of growth in the little mouse. , 1976, The Journal of endocrinology.

[10]  G. Barsh,et al.  The human growth hormone gene family: structure and evolution of the chromosomal locus. , 1983, Nucleic acids research.

[11]  S. Handwerger,et al.  Ovine placental lactogen induces somatomedin: a a possible role in fetal growth. , 1977, Endocrinology.

[12]  K. Yamamoto,et al.  Chromosomal position effects determine transcriptional potential of integrated mammary tumor virus DNA. , 1982, Journal of molecular biology.

[13]  W. Slidders.  The OFG and BrAB-OFG methods for staining the adenohypophysis. , 1961, The Journal of pathology and bacteriology.

[14]  R. Palmiter,et al.  A practical approach for quantitating specific mRNAs by solution hybridization. , 1983, Analytical biochemistry.

[15]  E. Spencer.  Lack of response of serum somatomedin to hyperprolactinemia in humans. , 1980, The Journal of clinical endocrinology and metabolism.

[16]  R. Palmiter,et al.  Regulation of metallothionein–thymidine kinase fusion plasmids injected into mouse eggs , 1982, Nature.

[17]  G. Rubin,et al.  The effect of chromosomal position on the expression of the drosophila xanthine dehydrogenase gene , 1983, Cell.

[18]  E. Froesch,et al.  The insulin-like growth factors (IGF) of human serum: chemical and biological characterization and aspects of their possible physiological role. , 1981, Current topics in cellular regulation.

[19]  D. Clemmons,et al.  The somatomedins: a family of insulinlike hormones under growth hormone control. , 1974, Recent progress in hormone research.

[20]  W. Daughaday,et al.  Somatomedin: Proposed Designation for Sulphation Factor , 1972, Nature.

[21]  S. Eden.  Age- and sex-related differences in episodic growth hormone secretion in the rat. , 1979, Endocrinology.

[22]  Michael G. Rosenfeld,et al.  Dramatic growth of mice that develop from eggs microinjected with metallothionein–growth hormone fusion genes , 1982, Nature.

[23]  R. Palmiter,et al.  Somatic expression of herpes thymidine kinase in mice following injection of a fusion gene into eggs , 1981, Cell.

[24]  Peter H. Seeburg,et al.  Nucleotide sequence and amplification in bacteria of structural gene for rat growth hormone , 1977, Nature.

[25]  U. Lewis,et al.  Studies of GH secretion in mice by a homologous radioimmunoassay for mouse GH. , 1972, Endocrinology.

[26]  W. Vale,et al.  Characterization of a growth hormone-releasing factor from a human pancreatic islet tumour , 1982, Nature.

[27]  J. V. Van Wyk,et al.  Sequence analysis of somatomedin-C: confirmation of identity with insulin-like growth factor I. , 1983, Endocrinology.

[28]  R. Palmiter,et al.  Transcriptional regulation of the mouse metallothionein-I gene by heavy metals. , 1981, The Journal of biological chemistry.

[29]  R. Palmiter,et al.  Structure of mouse metallothionein-I gene and its mRNA , 1981, Nature.