Comprehensive Physiology Wiley Online Library

Structure‐Function Relationships of Growth Hormone and Other Members of the Growth Hormone Gene Family

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Studies Using Growth Hormone Fragments
2 Multiple Activities of Growth Hormone
3 Crystal Structure
4 Studies Regarding Disulfide Bonds
5 Homologue/Alanine Scanning as A Means of Defining Biologically Active Domains
6 The Third α‐Helix
6.1 Mutagenesis of the Growth Hormone Gene Encoding α‐Helix 3 and Transgenic Mouse Studies
6.2 Importance of the Amphiphilicity of the Third α‐Helix
6.3 Designing a Growth Hormone Analogue with a Perfect Amphiphilic α‐Helix
6.4 Systematic Substitution Mutations in the Hydrophilic Region of the Third α‐Helix of Bovine Growth Hormone
7 Growth Hormone Antagonists
7.1 Pegylated Growth Hormone Antagonists as Therapeutic Agents
8 Finding of One Growth Hormone/Two Growth Hormone‐Binding Proteins
9 Mutagenesis Studies on the Prolactin Gene
10 Concluding Remarks
Figure 1. Figure 1.

Amino acid sequence identity comparison among the growth hormone (GH) molecules from various species . The x axis represents the GH amino acid sequence from different species. The y axis represents the percentage of amino acid sequence identity as compared to hGH.

Figure 2. Figure 2.

Amino acid sequence of the human growth hormone molecule: 191 amino acids along with the two disulfide bonds.

Adapted from Li and Bewley
Figure 3. Figure 3.

Schematic representation of bovine growth hormone. Arrows indicate the trypsin cleavage sites located between amino acids 96 and 97, 132 and 133. Also shown are three α‐helical regions.

From Hara et al.
Figure 4. Figure 4.

Crystal representation of the porcine growth hormone molecule at the 2.8 Å resolution level. Four α‐helices are depicted (cylindrical rods). The nonhelical region is shown as a thin tube. Also, one of the two disulfide bonds is shown, while the other is hidden behind α‐helix 4. The amino‐(N) and carboxyl (C) termini are located in the upper left and lower left corners, respectively.

From Abdel‐Meguid et al.
Figure 5. Figure 5.

Axial projection—that is, conversion of a linear amino acid sequence into a two‐dimentional representation—of the third α‐helix of native (A) and amino acid‐substituted (B) bovine growth hormone (bGH). Amino acid residues and corresponding hydrophilicity values are given. Amino acids in the open boxes are hydrophilic (top half of the wheel) and those in the shaded boxes are hydrophobic (bottom half). The glycine residue (position 119) is depicted with dots .

Figure 6. Figure 6.

Representative transgenic mice (2 months old, males) which express different (bGH) analogues. From left: transgenic mouse expressing bGH‐G119R; bGH‐A122D, which is similar in size to the nontransgenic mouse; and bGH‐E117L. All mice express ∼3–5 μg/ml of the bGH analogues in serum .

Figure 7. Figure 7.

Summary of transgenic mouse growth data . The x axis represents the individual transgenic lines. The y axis represents the mean growth ratio of pooled male and female transgenic mice between 2 and 4 months of age. Serum levels of bGH analogues ranged between 100 ng/ml and 10 μg/ml. There was no correlation between the serum levels of GH analogues and the degree of growth enhancement in transgenic animals with an enhanced‐growth phenotype. All standard deviations are within 15% of the mean.



Figure 1.

Amino acid sequence identity comparison among the growth hormone (GH) molecules from various species . The x axis represents the GH amino acid sequence from different species. The y axis represents the percentage of amino acid sequence identity as compared to hGH.



Figure 2.

Amino acid sequence of the human growth hormone molecule: 191 amino acids along with the two disulfide bonds.

Adapted from Li and Bewley


Figure 3.

Schematic representation of bovine growth hormone. Arrows indicate the trypsin cleavage sites located between amino acids 96 and 97, 132 and 133. Also shown are three α‐helical regions.

From Hara et al.


Figure 4.

Crystal representation of the porcine growth hormone molecule at the 2.8 Å resolution level. Four α‐helices are depicted (cylindrical rods). The nonhelical region is shown as a thin tube. Also, one of the two disulfide bonds is shown, while the other is hidden behind α‐helix 4. The amino‐(N) and carboxyl (C) termini are located in the upper left and lower left corners, respectively.

From Abdel‐Meguid et al.


Figure 5.

Axial projection—that is, conversion of a linear amino acid sequence into a two‐dimentional representation—of the third α‐helix of native (A) and amino acid‐substituted (B) bovine growth hormone (bGH). Amino acid residues and corresponding hydrophilicity values are given. Amino acids in the open boxes are hydrophilic (top half of the wheel) and those in the shaded boxes are hydrophobic (bottom half). The glycine residue (position 119) is depicted with dots .



Figure 6.

Representative transgenic mice (2 months old, males) which express different (bGH) analogues. From left: transgenic mouse expressing bGH‐G119R; bGH‐A122D, which is similar in size to the nontransgenic mouse; and bGH‐E117L. All mice express ∼3–5 μg/ml of the bGH analogues in serum .



Figure 7.

Summary of transgenic mouse growth data . The x axis represents the individual transgenic lines. The y axis represents the mean growth ratio of pooled male and female transgenic mice between 2 and 4 months of age. Serum levels of bGH analogues ranged between 100 ng/ml and 10 μg/ml. There was no correlation between the serum levels of GH analogues and the degree of growth enhancement in transgenic animals with an enhanced‐growth phenotype. All standard deviations are within 15% of the mean.

References
 1. Abdel‐Meguid, S. S., H. S. Shieh, W. W. Smith, H. E. Dayringer, B. N. Violand, and L. A. Bentle. Three‐dimensional structure of a genetically engineered variant of porcine growth hormone. Proc. Natl. Acad. Sci. USA 84: 6434–6437, 1987.
 2. Allen, T. M., C. Hansen, F. Martin, C. Redemann, and A. Y. Young. Liposomes containing synthetic lipid derivatives of poly(ethylene glycol) show prolonged circulation half‐lives in vivo. Biochim. Biophys. Acta 1066: 29–36, 1991.
 3. Altszuler, N., R. Steele, I. Rathgeb, and R. C. de Bodo. Glucose metabolism and plasma insulin levels during epinephrine infusion in the dog. Am. J. Physiol. 212: 677–682, 1967.
 4. Altszuler, N., R. Steele, I. Rathgeb, and R. C. de Bodo. Influence of growth hormone on glucose metabolism and plasma insulin levels in the dog. In: Growth Hormone, Proc. First Int. Symp., edited by A. Pecile and E. E. Muller. Amsterdam: Excerpta Med. 1968, p. 309–315. (Int. Congr. Ser. 158.)
 5. Armstrong, J. M., J. Bornstein, J. O. Bromley, S. L. Macaulay, and F. M. Ng. Parallel insulin‐like actions of human growth hormone and its part sequence hGH 7–13. Acta Endocrinol. (Copenh.) 102: 492–498, 1983.
 6. Aston, R., and J. Ivanyi. Antigenic, receptor binding and mitogenic activity of proteolytic fragments of human growth hormone. EMBO J. 2: 493–498, 1983.
 7. Barret, R. J., H. Freisen, and E. B. Astwood. Characterization of pituitary and peptide hormones by electrophoresis in starch gel. J. Biol. Chem. 237: 432–439, 1962.
 8. Batchelor, B. R., and R. J. Mahler. Growth hormone induced enhancement of insulin sensitivity in adipose tissue. Horm. Metab. Res. 12: 87–92, 1972.
 9. Baumann, G. Growth hormone binding proteins and various forms of growth hormone: implications for measurements. Acta Paediatr. Scand. Suppl. 370: 72–80, 1990.
 10. Baumann, G. Growth hormone heterogeneity: genes, isohormones, variants, and binding proteins. Endocr. Rev. 4: 424–449, 1991.
 11. Blanc, J. P., and E. T. Kaiser. Biological and physiological properties of a beta endorphin analog containing only d‐amino acids in the amphiphilic helical segment 13–31. J. Biol. Chem. 259: 9549–9556, 1984.
 12. Blanc, J. P., J. W. Taylor, R. J. Miller, and E. T. Kaiser. Examination of the requirement for an amphiphilic helical structure in beta endorphin through the design, synthesis, and study of model peptides. J. Biol. Chem. 258: 8277–8284, 1983.
 13. Cameron, C. M., J. L. Kosryo, J. A. Rillema, and S. E. Gennick. Reduced and S‐carboxymethylated human growth hormone: a probe for diabetogenic action. Am. J. Physiol. 247 (Endocrinol. Metab. 10): E639–E644, 1984.
 14. Campbell, R. M., J. L. Kostyo, and C. G. Scanes. Lipolytic and antilipolytic effects of human growth hormone, its 20‐kilodalton variant, a reduced and carboxymethylated derivative, and human placental lactogen on chicken adipose tissue in vitro. Proc. Soc. Exp. Biol. Med. 193: 269–273, 1990.
 15. Chen, C. H., and M. Sonenberg. Conformation studies of biologically active fragments of bovine growth hormone. Biochemistry 10: 2110–2118, 1977.
 16. Chen, N. Y., W. Y. Chen, L. Bellush, C. W. Yang, L. J. Striker, G. E. Striker, and J. J. Kopchick. Effects of streptozotocin treatment in growth hormone (GH) and GH antagonist transgenic mice. Endocrinology 136: 660–667, 1995.
 17. Chen, W. Y., N. Y. Chen, J. Yun, T. E. Wagner, and J. J. Kopchick. In vitro and in vivo studies of antagonistic effects of human growth hormone analogs. J. Biol. Chem. 269: 15892–15897, 1994.
 18. Chen, W. Y., N. Y. Chen, J. Yun, D. C. Wight, X. Z. Wang, T. E. Wagner, and J. J. Kopchick. Amino acid residues in the third alpha‐helix of growth hormone involved in growth promoting activity. Mol. Endocrinol. 9: 292–302, 1995.
 19. Chen, W. Y., M. E. White, T. E. Wagner, and J. J. Kopchick. Functional antagonism between endogenous mouse growth hormone (GH) and a GH analog results in transgenic dwarf mice. Endocrinology 129: 1402–1408, 1991.
 20. Chen, W. Y., D. C. Wight, N. Y. Chen, T. E. Wagner, and J. J. Kopchick. Mutations in the third α‐helix of bovine growth hormone dramatically affect its intracellular distribution in vitro and growth enhancement in transgenic mice. J. Biol. Chem. 266: 2252–2258, 1991.
 21. Chen, W. Y., D. C. Wight, B. V. Mehta, T. E. Wagner, and J. J. Kopchick. Glycine 119 of bovine growth hormone is critical for growth promoting activity. Mol. Endocrinol. 5: 1845–1852, 1991.
 22. Chen, W. Y., D. C. Wight, T. E. Wagner, and J. J. Kopchick. Expression of a mutated bovine growth hormone gene suppresses growth of transgenic mice. Proc. Natl. Acad. Sci. USA 8: 5061–5065, 1990.
 23. Chen, X. Z., A. W. Shafer, J. Yun, Y. S. Li, T. E. Wagner, and J. J. Kopchick. Conversion of bovine growth hormone cysteine residues to serine affects secretion by cultured cells and growth rates in transgenic mice. Mol. Endocrinol. 6: 598–606, 1992.
 24. Chou, P. Y., and G. D. Fasman. Prediction of protein conformation. Biochemistry 13: 222–245, 1974.
 25. Cunningham, B. C., G. Fuh, and J. A. Wells. Zinc mediation of the binding of human growth hormone to the human prolactin receptor. Science 250: 1709–1712, 1990.
 26. Cunningham, B. C., P. Jhurani, P. Ng, and J. A. Wells. Receptor and antibody epitopes in human growth hormone identified by homolog‐scanning mutagenesis. Science 243: 1330–1336, 1989.
 27. Cunningham, B. C., and J. A. Wells. High‐resolution epitope mapping of hGH‐receptor interaction by alanine‐scanning mutagenesis. Science 244: 1081–1085, 1989.
 28. Dattani, M. T., P. C. Hindmarsh, C.G.D. Brook, I.C.A.F. Robinson, J. J. Kopchick, and N. J. Marshall. G120R, a human growth hormone antagonist, shows zinc‐dependent agonist and antagonist activity on Nb2 cells. J. Biol. Chem. 270: 9222–9226, 1995.
 29. De Bodo, R., and N. Altszuler. The metabolic effects of growth hormone and their physiological significance. Vitam. Horm. 15: 206–211, 1957.
 30. De Vos, A., M. Ultsch, and A. A. Kosslakoff. Human growth hormone and extracellular domain of its receptor: crystal structure of the complex. Science 255: 306–312, 1992.
 31. Digel, M. B., N. A. Thorpe, M.S. Kobrin, U.J. Lewis, and W. P. VanderLaan. Binding characteristics of a biologically active variant of human growth hormone (20K) to growth hormone and lactogen receptors. Endocrinology 108: 1600–1603, 1981.
 32. Dixon, J. S., and C. H. Li. Retention of the biological potency of human pituitary growth hormone after reduction and carbamidomethylation. Science 154: 785–786, 1966.
 33. Doneen, B. A., T. A. Bewley, and C. H. Li. Studies on prolactin. Selective reduction of the disulfide bonds of the bovine hormone. Biochemistry 18: 4851–4860, 1979.
 34. Edmunson, A. B. Amino‐acid sequence of sperm whale myoglobin. Nature 205: 883–887, 1965.
 35. Evans, H. M., and J. A. Long. The effect of the anterior lobe administered intraperitoneally upon growth, maturity and oestrus cycles of the rat. Anat. Rec. 21: 62–63, 1921.
 36. Fain, J. H., V. P. Kovacev, and R. O. Scow. Effect of growth hormone and dexamethasone on lipolysis and metabolism in isolated fat cells of the rat. J. Biol. Chem. 240: 3522–3528, 1965.
 37. Foley, E. D., L. P. Aiello, E. A. Pierce, R. Sullivan, W. Y. Chen, J. R. Knapp, J. J. Kopchick, and L.E.H. Smith. The effect of growth hormone on a mouse model of proliferative retinopathy [Abstract]. Invest. Ophthalmol. Vis. Sci. 36: S1047, 1995.
 38. Fraser, R., J. F. Joplin, M. Opie, and D. Rawbinowitz. The augmented insulin tolerance test for detecting insulin resistance. J. Endocrinol. 25: 299–303, 1962.
 39. Frigeri, L. G., S. M. Peterson, and U. J. Lewis. The 20,000 dalton structural variant of human growth hormone: lack of some early insulin‐like effects. Biochem. Biophys. Res. Commun. 91: 778–782, 1979.
 40. Fuh, G., P. Colosi, W. I. Wood, and J. A. Wells. Mechanism‐based design of prolactin receptor antagonists. J. Biol. Chem. 268: 5376–5381, 1993.
 41. Fuh, G., B.C. Cunningham, R. Fukunaga, S. Nagata, D. V. Goeddel, and J. A. Wells. Rational design of potent antagonists to the human growth hormone receptor. Science 256: 1677–1680, 1992.
 42. Garnier, J., D. J. Osguthorpe, and B. Robson. Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins. J. Mol. Biol. 120: 97–120, 1978.
 43. Goffin, V., M. Norman, and J. A. Martial. Alanine scanning mutagenesis of human prolactin: importance of the 58–74 region for bioactivity. Mol. Endocrinol. 6: 1381–1392, 1992.
 44. Goffin, V., I. Struman, E. Doodmaghtigh, and J. A. Martial. The addition of nine residues at the C‐terminus of human prolactin drastically alters its biological properties. Eur. J. Biochem. 214: 483–490, 1993.
 45. Goffin, V., I. Struman, V. Mainfroid, S. Kinet, and J. A. Martial. Evidence for a second receptor binding site on human prolactin. J. Biol. Chem. 269: 32598–32606, 1994.
 46. Goodman, H. M. Effects of growth hormone on the utilization of l‐leucine in adipose tissue. Endocrinology 76: 210–217, 1978.
 47. Goodman, H. M., and G. Grichting. Growth hormone and lipolysis: a reevaluation. Endocrinology 113: 1697–1702, 1983.
 48. Goodman, H. M., G. Grichting, and V. Coiro. Growth hormone action on adipocytes. In: Human Growth Hormone, edited by S. Raiti and R. H. Tolman. New York: Plenum, 1986, p. 499–512.
 49. Goodman, H. M., and J. Schwartz. Growth hormone and lipid metabolism. In: Handbook of Physiology. Endocrinology. The Pituitary Gland and Its Neuroendocrine Control, of Physiology edited by E. Knobil and W. H. Sawyer. Washington, D.C.: Am. Physiol. Soc., 1974, sect. 7, vol. 4, pt. 2, p. 211–232.
 50. Graf, L., C. H. Li, and T. A. Bewley. Selective reduction and alkylation of the COOH‐terminal disulfide bridge in bovine growth hormone. Int. J. Peptide Protein Res. 7: 467–473, 1975.
 51. Greenspan, F. S., C. H. Li, M. E. Simpson, and H. M. Evans. Bioassay of hypophyseal growth hormone: the tibia test. Endocrinology 45: 455–463, 1949.
 52. Hara, K., C. J. H. Chen, and M. Sonenberg. Recombination of the biologically active peptides from a tryptic digest of bovine growth hormone. Biochemistry 17: 550–556, 1978.
 53. Hara, K., and M. Sonenberg. Polyalanylation of bovine somatotropin peptide 96–133. Biochim. Biophys. Acta 492: 95–101, 1977.
 54. Hjalmarson, A., and K. Ahren. Sensitivity of the rat diaphragm to growth hormone. Acta Endocrinol. (Copenh.) 56: 347–358, 1967.
 55. Hollobaugh, D. L., M. Tzagournis, R. L. Folk, F. A. Kruger, and G. J. Hamwi. The diabetogenic action of human growth hormone: glucose fatty acid interrelationships. Metabolism 17: 485–491, 1968.
 56. Hopp, T. P., and K. R. Woods. Prediction of protein antigenic determinants from amino acid sequences. Proc. Natl. Acad. Sci. USA 78: 3824–3828, 1981.
 57. Inoue, H., T. Kadoya, K. Kabaya, K. Tachibana, N. Nishi, M. Sato, M. Ohsawa, T. Mikayama, and K. J. Mori. A highly enhanced thrombopoietic activity by monomethoxy polyethylene glycol‐modified recombinant human interleukin‐6. J. Lab. Clin. Med. 124: 529–536, 1994.
 58. Isaksson, O., D. F. Nutting, J. L. Kostyo, and C. R. Reagan. Hourly variations in plasma concentrations of growth hormone and insulin and in amino acid uptake and incorporation into protein in diaphragm muscle of the rat. Endocrinology 102: 1420–1428, 1978.
 59. Ishikawa, M., Y. Okada, R. S. Ishikawa, M. Kakitani, M. Kawagishi, S. Matsuki, M. Kusaka, and K. Asano. Pharmacological effects of recombinant human granulocyte colony‐stimulating factor modified by polyethylene glycol on anticancer drug‐induced neutropenia in mice. Gen. Pharmacol. 25: 533–537, 1994.
 60. Jeoung, D. I., D. L. Allen, S. Guller, V. Yen, and M. Sonenberg. Mitogenic and receptor activities of human growth hormone 108–129. J. Biol. Chem. 268: 22520–22524, 1993.
 61. Jin, L., and J. A. Wells. Dissecting the energetics of an antibody‐antigen interface by alanine shaving and molecular grafting. Protein Sci. 3: 2351–2357, 1994.
 62. Kaiser, E. T., and F. J. Kezdy. Amphiphilic secondary structure: design of peptide hormones. Science 223: 249–255, 1984.
 63. Kaplan, S. L., and M. M. Grumbach. Electrophoretic and immunological characteristics of native and purified human growth hormone. Nature 196: 336–338, 1962.
 64. Klibanov, A. L., K. Maruyama, A. M. Beckerleg, V. P. Torchilin, and L. Huang. Activity of amphipathic poly(ethylene glycol) 5000 to prolong the circulation time of liposomes depends on the liposome size and is unfavorable for immunoliposome binding to target. Biochim. Biophys. Acta 1062: 142–148, 1991.
 65. Kostyo, J. L. The search for the active core of pituitary growth hormone [Review]. Metabolism 23: 885–899, 1974.
 66. Kostyo, J. L. The multivalent nature of growth hormone. In: Human Growth Hormone, edited by S. Raiti and R. H. Tolman. New York: Plenum, 1986, p. 449–454.
 67. Kostyo, J. L., C. M. Cameron, K. C. Olson, A. J. Jones, and R. C. Pai. Biosynthetic 20‐kilodalton methionyl‐human growth hormone has diabetogenic and insulin‐like activities. Proc. Natl. Acad. Sci. USA 82: 4250–4253, 1985.
 68. Kostyo, J. L., S. E. Gennick, and S. E. Sauder. Diabetogenic activity of native and biosynthetic human growth hormone in obese (ob/ob) mouse. Am. J. Physiol. 246 (Endocrinol. Metab. 9): E356–360, 1984.
 69. Kostyo, J. L., and D. F. Nutting. Acute in vivo actions of growth hormone on protein synthesis in various tissues of hypophysectomized rats and their relationship to the levels of thymidine factor and insulin in the plasma. Horm. Metab. Res. 5: 167–172, 1973.
 70. Kostyo, J. L., and D. F. Nutting. Growth hormone and protein metabolism. In: Handbook of Physiology. Endocrinology. The Pituitary Gland and Its Neuroendocrine Control, edited by E. Knobil and W. H. Sawyer. Washington, D.C.: Am. Physiol. Soc., sect. 7, vol. 4, pt. 2, 1974, p. 187–210.
 71. Leung, F. C., B. Jones, S. L. Steelman, C. I. Rosenblum, and J. J. Kopchick. Purification and physiochemical properties of a recombinant bovine growth hormone produced by cultured murine fibroblasts. Endocrinology 119: 1489–1496, 1986.
 72. Levine, L., M. Sonenberg, and M. E. New. Metabolic effects in children of a 37 amino acid fragment of bovine growth hormone. J. Clin. Endocrinol. Metab. 37: 607–615, 1973.
 73. Lewis, U. J. Enzymatic transformations of growth hormone and prolactin. J. Biol. Chem. 237: 3141–3145, 1962.
 74. Lewis, U. J., and N. C. Brink. Crystalline human growth hormone. J. Am. Chem. Soc. 80: 4429–4430, 1958.
 75. Lewis, U. J., E. V. Cheever, and W. C. Hopkins. Kinetic study of the deamidation of growth hormone and prolactin. Biochim. Biophys. Acta 214: 498–508, 1970.
 76. Lewis, U. J., J. T. Dunn, B. K. Bonewald, B. K. Seavey, and W. P. VanderLaan. A naturally occurring structural variant of human growth hormone. J. Biol. Chem. 253: 2679–2683, 1978.
 77. Li, C. H. The chemistry of human pituitary growth hormone: 1967–1973. In: Hormonal Proteins and Peptides, edited by C. H. Li. New York: Academic, 1975, vol. 3, p. 1–33.
 78. Li, C. H, and T. A. Bewley. Human pituitary growth hormone: restoration of full biological activity by noncovalent interaction of two fragments of the hormone. Proc. Natl. Acad. Sci. USA 73: 1476–1479, 1976.
 79. Li, C. H., and H. M. Evans. The isolation of pituitary growth hormone. Science 99: 183–184, 1944.
 80. Li, C. H., and L. Graf. Human pituitary growth hormone isolation and properties of two biologically active fragments from plasmin digests. Proc. Natl. Acad. Sci. USA 71: 1197–1201, 1974.
 81. Li, C. H., W. K. Liu, and J. S. Dixon. Human pituitary growth hormone. VI. Modified procedure of isolation and NH2‐terminal amino acid sequence. Arch. Biochem. Biophys. (Suppl. 1): 327–332, 1962.
 82. Luck, D. N., M. Huyer, P. W. Gout, C. T. Beer, and M. Smith. Single amino acid substitutions in recombinant bovine prolactin that markedly reduce its mitogenic activity in Nb2 cell cultures. Mol. Endocrinol. 5: 1880–1886, 1991.
 83. Lyons, W. R. Preparation and assay of mammotropic hormone. Proc. Soc. Exp. Biol. Med. 35: 645–648, 1937.
 84. MacGorman, C. R., R. A. Rizza, and J. E. Gerich. Physiological concentrations of growth hormone exert insulin‐like and insulin antagonistic effects on both hepatic and extrahepatic tissues in man. J. Clin. Endocrinol. Metab. 53: 556–559, 1981.
 85. Maloff, B. L., J. H. Levine, and D. H. Lockwood. Direct effects of growth hormone on insulin action in rat adipose tissue maintained in vitro. Endocrinology 107: 538–544, 1980.
 86. Malik, F., C. Delgado, C. Knusli, A. E. Irvine, D. Fisher, and G. E. Francis. Polyethylene glycol (PEG)‐modified granulocyte macrophage colony‐stimulating factor (GM‐CSF) with conserved biological activity. Exp. Hematol. 20: 1028–1035, 1992.
 87. Maruyama, O., T. Kato, K. Wakabayashi, and Y. Kato. Amino acids in the amino terminal region of the rat prolactin contribute to PRL‐receptor binding and Nb2 cell proliferation activity. Biochem. Biophys. Res. Commun. 205: 312–319, 1994.
 88. Meyers, F. J., C. Paradise, S. A. Scudder, G. Goodman, and M. Konrad. A phase I study including pharmacokinetics of polyethylene glycol conjugated interleukin‐2. Clin. Pharmacol. Ther. 49: 307–313, 1991.
 89. Mills, J. B., J. L. Kostyo, M. H. Moseley, C. R. Reagan, and A. E. Wilhelmi. Isolation and characterization of fragments of reduced and S‐carbamidomethylated human growth hormone produced by plasmin digestion. I. Chemistry. Endocrinology 102: 1366–1376, 1978.
 90. Mills, J. B., J. L. Kostyo, C. R. Reagan, S. A. Wagner, M. H. Moseley, and A. E. Wilhelmi. Fragments of human growth hormone produced by digestion with thrombin: chemistry and biological properties. Endocrinology 107: 391–399, 1980.
 91. Miller, L. W., and N. L. Eberhardt. Structure and evolution of the growth hormone gene family. Endocr. Rev. 4: 97–129, 1983.
 92. Milman, A. E., and J. A. Russell. Some aspects of purified pituitary growth hormone on carbohydrate metabolism in the rat. Endocrinology 47: 114–119, 1950.
 93. Mode, A., P. Toilet, T. Wells, D. F. Carmignac, R. G. Clark, W. Y. Chen, J. J. Kopchick, and I. C. A. F. Robinson. The human growth hormone (hGH) antagonist G120R hGH does not antagonize GH in the rat, but has paradoxical agonist activity, probably via the prolactin receptor. Endocrinology 137: 447–454, 1996.
 94. Moe, G. R., and E. T. Kaiser. Design, synthesis and characterization of a model peptide having potent calcitonin‐like biological activity: implications for calcitonin structure/activity. Biochemistry 24: 1971–1976, 1985.
 95. Moe, G. R., R. J. Miller, and E. T. Kaiser. Design of a peptide hormone: synthesis and characterization of a model peptide with calcitonin‐like activity. J. Am. Chem. Soc. 105: 4100–4102, 1983.
 96. Necessary, P. C., T. T. Anderson, and K. E. Ebner. Activity of alkylated prolactin and human growth hormone in receptor and cell assays. Mol. Cell. Endocrinol. 39: 247–254, 1985.
 97. Newman, J. D., J. Armstrong, and J. Bornstein. Effects of part sequences of human growth hormone on in vivo hepatic glycogen metabolism in the rat. Biochim. Biophys. Acta 544: 234–244, 1978.
 98. Ng, F. M., and J. Bornstein. Insulin‐potentiating action of a synthetic amino‐terminal fragment of human growth hormone (hGH 1–15) in streptozotocin‐diabetic rats. Diabetes 28: 1126–1130, 1979.
 99. Ng, F. M., J. Bornstein, C. Welker, P. Z. Zimmet, and P. Taft. Insulin potentiating action of synthetic peptides relating to the amino terminal sequence of human growth hormone. Diabetes 23: 943–949, 1974.
 100. Ng, F. M., and J. A. Jarcourt. Stimulation of 2‐deoxyglucose uptake in rat adipocytes by a human growth hormone fragment (hGH 4–15). Diabetologia 29: 882–887, 1986.
 101. Niall, H. D., M. L. Hogan, R. Sayer, I. Y. Rosenblum, and R. C. Greenwood. Sequences of pituitary and placental lactogenic hormone. Proc. Natl. Acad. Sci. USA 68: 866–869, 1971.
 102. Nicoll, C. S. Bio‐assay of prolactin. Analysis of the pigeon crop‐sac response to local prolactin injection by an objective and quantitative method. Endocrinology 80: 641–655, 1967.
 103. Nicoll, C. S., G. L. Mayer, and S. M. Russell. Structural features of prolactins and growth hormones that can be related to their biological properties. Endocr. Rev. 7: 169–203, 1986.
 104. Nutting, D. F., J. L. Kostyo, J. B. Mills, and A. E. Wilhelmi. A cyanogen bromide fragment of reduced and S‐aminoethylated porcine growth hormone with anabolic activity. Biochim. Biophys. Acta 200: 601–604, 1970.
 105. Okada, S., W. Y. Chen, P. Wiehl, B. Kelder, H. M. Goodman, S. Guller, M. Sonenberg, and J. J. Kopchick. A growth hormone (GH) analog can antagonize the ability of native GH to promote differentiation of 3T3–F442A preadipocytes and to stimulate insulin‐like and lipolytic activities in primary rat adipocytes. Endocrinology 130: 2284–2290, 1992.
 106. Paladini, A. C., C. Pena, and E. Parks. Molecular biology of growth hormone. CRC Crit. Rev. Biochem. 15: 25–56, 1984.
 107. Pandian, M. R., S. L. Gupta, and G. P. Talway. Studies on the early interactions of growth hormone: effect in vitro on lipogenesis in adipose tissue. Endocrinology 88: 928–932, 1971.
 108. Porterfield, S. P. The effects of growth hormone, thyroxine and insulin on the activities of reduced nicotinamide adenine dinucleotide phosphate dehydrogenase, glucose‐6‐phosphatase and glycogen phosphorylase in fetal rat liver. Horm. Metab. Res. 11: 444–448, 1979.
 109. Reagan, C. R., J. L. Kostyo, J. B. Mills, S. E. Gennick, J. L. Messina, S. A. Wagner, and A. E. Wilhelmi. Recombination of fragments of human growth hormone: altered activity profile of the recombinant molecule. Endocrinology 109: 1663–1671, 1981.
 110. Reagan, C. R., J. L. Kostyo, J. B. Mills, M. H. Moseley, and A. E. Wilhelmi. Isolation and characterization of fragments of reduced and S‐carbamidomethylated human growth hormone produced by plasmin digestion. II. Biological and immunological activities. Endocrinology 102: 1377–1386, 1978.
 111. Reagan, C. R., M. H. Mills, J. L. Kostyo, and A. E. Wilhelmi. Biological properties of plasmin digests of S‐carbamidomethylated human growth hormone. Proc. Natl. Acad. Sci. USA 72: 1684–1686, 1975.
 112. Reagan, C. R., M. H. Mills, J. L. Kostyo, and A. E. Wilhelmi. Isolation and biological characterization of fragments of human growth hormone produced by digestion with plasmin. Endocrinology 96: 625–636, 1975.
 113. Reisfeld, R. A., B. G. Hallows, D. E. Williams, N. G. Brink, and S. L. Steelman. Purification of human growth hormone on “Sephadex G‐200.” Nature 97: 1206–1207, 1963.
 114. Rhee, H. K., Z. Sun, S. S. Kim, V. Goffin, J. A. Martial, and P. S. Dannies. Biological activity and immunological reactivity of human prolactin mutants. Endocrinology 136: 4990–4995, 1995.
 115. Roos, P., H. R. Fevold, and C. A. Gemzell. Preparation of human growth hormone by gel filtration. Biochim. Biophys. Acta 74: 525–531, 1965.
 116. Rowlinson, S. W., B. Ross, S. Bastiras, A. J. Robins, R. Brinkworth, and M. J. Waters. A growth hormone agonist produced by targeted mutagenesis at binding site 1: evidence that site 1 regulates bioactivity. J. Biol. Chem. 270: 16833–16839, 1995.
 117. Russell, J., L. M. Sherwood, K. Kowalski, and A. B. Schneider. Recombinant hormones from fragments of human growth hormone and human placental lactogen. J. Biol. Chem. 256: 296–300, 1981.
 118. Salem, M. A. Effects of the amino‐terminal portion of human growth hormone on glucose clearance and metabolism in normal, diabetic, hypophysectomized, and diabetic–hypophysectomized rats. Endocrinology 123: 1565–1576, 1988.
 119. Scanes, C. G., and R. M. Campbell. Growth hormone: chemistry. In: Growth Hormone, edited by S. Harvey, C. G. Scanes, and W. H. Daughaday. Boca Raton, FL: CRC, 1995, p. 1–24.
 120. Shaar, C. J., E. L. Grinnan, W. G. Short, J. G. Powell, N. Bryan, K. G. Bemis, and F. C. Tinsley. Hyperglycemic activity in dogs of recombinant DNA‐derived 20,000 dalton variant of methionyl human growth‐hormone. Endocr. Res. 12: 21–32, 1986.
 121. Smal, J., J. Closset, G. Hennen, and P. De Meyts. The receptor binding properties of the 20K variant of human growth hormone explain its discrepant insulin‐like and growth promoting activities. Biochem. Biophys. Res. Commun. 134: 159–165, 1986.
 122. Sonenberg, M., M. Kitkutani, C. A. Free, A. C. Nadler, and J. M. Dellacha. Chemical and biochemical characterization of clinically active tryptic digests of bovine growth hormone. Ann. N. Y. Acad. Sci. 148: 532–558, 1968.
 123. Stanojevic, D., and G. L. Verdine. Deconstruction of GCN4/ GCRE into a monomeric peptide–DNA complex. Nat. Struct. Biol. 2: 450–457, 1995.
 124. Stewart, T. A., S. Clift, S. Pitts‐Meek, L. Martin, T. G. Terrell, D. Liggitt, and H. Oakley. An evaluation of the functions of the 22‐kilodalton (kDa), the 20‐kDa, and the N‐terminal polypeptide forms of human growth hormone using transgenic mice. Endocrinology 130: 405–414, 1992.
 125. Swislocki, N. L. Effects of nutritional status and the pituitary on the acute plasma free fatty acid and glucose reponses of rats to growth hormone administration. Metabolism 17: 174–180, 1968.
 126. Tokunaga, T., T. Tanaka, M. Kehara, and E. Ohtsuka. Synthesis and expression of a human growth hormone (somatotropin) gene mutated to change cysteine‐165 to alanine. Eur. J. Biochem. 153: 445–449, 1985.
 127. Tou, J. S., L. A. Kaempfe, B. D. Vinegard, F. C. Buonomo, M. A. Della‐Fera, and C. A. Baile. Amphiphilic growth hormone releasing factor analogs: peptide design and biological activity in vivo. Biochem. Biophys. Res. Commun. 139: 763–770, 1986.
 128. Towns, R., J. L. Kostyo, T. Vogel, E. Sakal, A. Tchelet, R. Maher, and A. Gertler. Evidence that the N‐terminus of human growth hormone is involved in expression of its growth promoting, diabetogenic, and insulin‐like activities. Endocrinology 130: 1225–1230, 1992.
 129. Tsutsumi, Y., T. Kihira, S. Tsunoda, K. Kubo, M. Miyake, T. Kanamori, S. Nakagawa, and T. Mayumi. Intravenous administration of polyethylene glycol‐modified tumor necrosis factor‐alpha completely regressed solid tumor in Meth‐A murine sarcoma model. Jpn. J. Cancer Res. 85: 9–12, 1994.
 130. Wade, J. D., F. M. Ng, J. Bornstein, C. O. Purlin, and J. S. Pearce. Effect of C‐terminal chain shortening on the insulin‐antagonistic activity of human growth hormone 177–191. Acta Endocrinol. (Copenh.) 101: 10–14, 1982.
 131. Wade, J. D., C. O. Pullin, F. M. Ng, and J. Bornstein. The synthesis and hyperglycemic activity of the amino acid sequence 172–191 of human growth hormone. Biochem. Biophys. Res. Commun. 78: 827–833, 1977.
 132. Wallace, A. L. C., and K. A. Ferguson. Preparation of human growth hormone. J. Endocrinol. 23: 285–290, 1961.
 133. Wallis, M. The chemistry of pituitary growth hormone, prolactin and related hormones and its relationship to biological activity. In: Chemistry and Biochemistry of Amino Acids, Peptides and Proteins, edited by B. Weinstein. New York: Marcel Dekker, 1978, vol. 5, p. 213–233.
 134. Watahiki, M. Yamamoto, M. Yamakawa, M. Tanaka, and K. Nakashima. Conserved and unique amino acid residues in the domains of the growth hormones. J. Biol. Chem. 264: 312–316, 1989.
 135. Xing, H., and D.J. Shapiro. An estrogen receptor mutant exhibiting hormone‐independent transactivation and enhanced affinity for the estrogen response element. J. Biol. Chem. 268: 23227–23233, 1993.
 136. Yamaoka, T., Y. Tabata, and Y. Ikada. Distribution and tissue uptake of poly(ethylene glycol) with different molecular weights after intravenous administration to mice. J. Pharm. Sci. 83: 601–606, 1994.
 137. Yamasaki, N., K. Kangawa, S. Kobayashi, M. Kikutani, and M. Sonenberg. Amino acid sequence of a biologically active fragment of bovine growth hormone. J. Biol. Chem. 247: 3874–3880, 1972.
 138. Yamasaki, N., J. Shimanaka, and M. Sonenberg. Studies on the common active site of growth hormone: revision of the amino acid sequence of an active fragment of bovine growth hormone. J. Biol. Chem. 250: 2510–2514, 1975.
 139. Yang, C. W., L. J. Striker, J. J. Kopchick, W. Y. Chen, C. M. Pesce, E. P. Peten, and G. E. Striker. Glomerulosclerosis in mice transgenic for native or mutated bovine growth hormone. Kidney Int. 43: 90–94, 1993.
 140. Yang, C. W., L. J. Striker, C. Pesce, W. Y. Chen, E. P. Paten, S. Elliot, T. Doi, J. J. Kopchick, and G. E. Striker. Glomerulosclerosis and body growth are mediated by different portions of bovine growth hormone: studies in transgenic mice. Lab. Invest. 68: 62–72, 1993.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

John J. Kopchick, Wen Y. Chen. Structure‐Function Relationships of Growth Hormone and Other Members of the Growth Hormone Gene Family. Compr Physiol 2011, Supplement 24: Handbook of Physiology, The Endocrine System, Hormonal Control of Growth: 145-162. First published in print 1999. doi: 10.1002/cphy.cp070506