Skip to main content

Advertisement

Springer Nature Link
Log in

Zip1, Zip2, and Zip8 mRNA Expressions Were Associated with Growth Hormone Level During the Growth Hormone Provocation Test in Children with Short Stature

  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

Short stature of children is affected by multiple factors. One of them is growth hormone (GH) deficiency. Growth hormone therapy can increase the final height of children with growth hormone deficiency. Zinc is found to induce dimerization and to enhance the bioactivity of human GH. Two gene families have been identified involved in zinc homeostasis. Previous studies in our laboratory have shown that Zip1, Zip2, Zip6, and ZnT1 mRNA were associated with zinc level in established human breast cancer in nude mice model; Zip8 was significantly lower in zinc-deficient Wistar rats in kidney. In this study, five zinc transporters: Zip1, Zip2, Zip6, Zip8, and ZnT1 were chosen. We aimed to investigate the mRNA expression of zinc transporters and to explore the relationship between zinc transporters and growth hormone in short stature children. Growth hormone provocation test is used to confirm the diagnosis of growth hormone deficiency. Six short children for the test were enrolled. At the same time, 15 sex- and age-matched normal children were enrolled as control. The expression levels of zinc transporters in peripheral blood mononuclear cells were determined by quantitative real-time PCR. Zip1 and Zip2 mRNA expression positively correlated with growth hormone level (r = 0.5133, P = 0.0371; r = 0.6719, P = 0.0032); Zip8 mRNA expression negatively correlated with growth hormone level (r = −0.5264, P = 0.0285) during the test in short stature children. The average expression level of Zip2 was significantly higher and Zip6, Zip8 mRNA levels were significantly lower in short stature children than in health controls at 0 min (P < 0.05, P < 0.05).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+
from $39.99 /Month
  • Starting from 10 chapters or articles per month
  • Access and download chapters and articles from more than 300k books and 2,500 journals
  • Cancel anytime
View plans

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Explore related subjects

Discover the latest articles, books and news in related subjects, suggested using machine learning.

References

  1. Cohen P, Rogol AD, Deal CL, Saenger P, Reiter EO, Ross JL et al (2008) Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. J Clin Endocrinol Metab 93(11):4210–4217. doi:10.1210/jc.2008-0509

    Article  PubMed  CAS  Google Scholar 

  2. Greenwood FC, Landon J, Stamp TC (1966) The plasma sugar, free fatty acid, cortisol, and growth hormone response to insulin. I. In control subjects. J Clin Invest 45(4):429–436

    Article  PubMed  CAS  Google Scholar 

  3. Vallee BL, Auld DS (1990) Zinc coordination, function, and structure of zinc enzymes and other proteins. Biochemistry 29(24):5647–5659

    Article  PubMed  CAS  Google Scholar 

  4. Fukada T, Yamasaki S, Nishida K, Murakami M, Hirano T (2011) Zinc homeostasis and signaling in health and diseases: zinc signaling. J Biol Inorg Chem 16(7):1123–1134

    Article  PubMed  CAS  Google Scholar 

  5. Maret W (2011) Metals on the move: zinc ions in cellular regulation and in the coordination dynamics of zinc proteins. Biometals 24(3):411–418

    Article  PubMed  CAS  Google Scholar 

  6. Prasad AS (1995) Zinc: an overview. Nutrition 11:93–99

    PubMed  CAS  Google Scholar 

  7. Plum LM, Rink L, Haase H (2010) The essential toxin: impact of zinc on human health. Int J Environ Res Public Health 7(4):1342–1365

    Article  PubMed  CAS  Google Scholar 

  8. Gaither LA, Eide DJ (2001) Eukaryotic zinc transporters and their regulation. BioMetals 14(3–4):251–270

    Article  PubMed  CAS  Google Scholar 

  9. Kambe T, Yamaguchi-Iwai Y, Sasaki R, Nagao M (2004) Overview of mammalian zinc transporters. Cell Mol Life Sci 61(1):49–68

    Article  PubMed  CAS  Google Scholar 

  10. Dufner-Beattie J, Huang ZL, Geiser J, Xu W, Andrews GK (2006) Mouse ZIP1 and ZIP3 genes together are essential for adaptation to dietary zinc deficiency during pregnancy. Genesis 44(5):239–251

    Article  PubMed  CAS  Google Scholar 

  11. Küry S, Dréno B, Bézieau S, Giraudet S, Kharifi M et al (2002) Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Nat Genet 31(3):239–240

    Article  PubMed  Google Scholar 

  12. Fukada T, Civic N, Furuichi T, Shimoda S, Mishima K, Higashiyama H et al (2008) The zinc transporter SLC39A13/ZIP13 is required for connective tissue development; its involvement in BMP/TGF-beta signaling pathways. PLoS One 3(11):e3642

    Article  PubMed  Google Scholar 

  13. Hojyo S, Fukada T, Shimoda S, Ohashi W, Bin BH, Koseki H et al (2011) The zinc transporter SLC39A14/ZIP14 controls G-protein coupled receptor-mediated signaling required for systemic growth. PLoS One 6(3):e18059

    Article  PubMed  CAS  Google Scholar 

  14. Inoue K, Matsuda K, Itoh M, Kawaguchi H, Tomoike H, Aoyagi T et al (2002) Osteopenia and male-specific sudden cardiac death in mice lacking a zinc transporter gene, Znt5.Hum. Mol Genet 11(15):1775–1784

    CAS  Google Scholar 

  15. Huang L, Yu YY, Kirschke CP, Gertz ER, Lloyd KK (2007) Znt7 (Slc30a7)-deficient mice display reduced body zinc status and body fat accumulation. J Biol Chem 282(51):37053–37063

    Article  PubMed  CAS  Google Scholar 

  16. Wenzlau JM, Juhl K, Yu L, Moua O, Sarkar SA et al (2007) The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci USA 104(43):17040–17045

    Article  PubMed  CAS  Google Scholar 

  17. Burczynski ME, Dorner AJ (2006) Transcriptional profiling of peripheral blood cells in clinical pharmacogenomic studies. Pharmacogenomics 7(2):187–202

    Article  PubMed  CAS  Google Scholar 

  18. Murgia C, Grosser D, Truong-Tran AQ, Roscioli E, Michalczyk A, Ackland ML et al (2011) Apical localization of zinc transporter ZnT4 in human airway epithelial cells and its loss in a murine model of allergic airway inflammation. Nutrients 3(11):910–928

    Article  PubMed  CAS  Google Scholar 

  19. Wit JM, Clayton PE, Rogol AD, Savage MO, Saenger PH, Cohen P (2008) Idiopathic short stature: definition, epidemiology, and diagnostic evaluation. Growth Horm IGF Res 18(2):89–110. doi:10.1016/j.ghir.2007.11.004

    Article  PubMed  CAS  Google Scholar 

  20. Edouard T, Grünenwald S, Gennero I, Salles JP, Trauber M (2009) Prevalence of IGF1 deficiency in prepubertal children with isolated short stature. Eur J Endocrinol 161(1):43–50. doi:10.1530/EJE-08-0964

    Article  PubMed  CAS  Google Scholar 

  21. Hashemi J, Hajiani E, Shahbazin HB, Masjedizadeh R, Ghasemi N (2008) Prevalence of celiac disease in Iranian children with idiopathic short stature. World J Gastroenterol 14(48):7376–7380

    Article  PubMed  Google Scholar 

  22. Majcher A, Witkowska-Sędek E, Bielecka-Jasiocha J, Pyrżak B (2012) Causes of short stature in children in relation to their midparental height. Med Wieku Rozwoj 16(2):89–95

    PubMed  Google Scholar 

  23. Bright GM, Veldhuis JD, Iranmanesh A, Baumann G, Maheshwari H, Lima J (1999) Appraisal of growth hormone (GH) secretion: evaluation of a composite pharmacokinetic model that discriminates multiple components of GH input. J Clin Endocrinol Metab 84(9):3301–3308

    Article  PubMed  CAS  Google Scholar 

  24. Laron Z, Silbergeld A, Kauli R (2012) Differential effects of hGH and IGF-I on body proportions. Anthropol Anz 69(3):255–259

    Article  PubMed  Google Scholar 

  25. Cunningham BC, Mulkerrin MG, Wells JA (1991) Dimerization of human growth hormone by zinc. Science 253(5019):545–548

    Article  PubMed  CAS  Google Scholar 

  26. Dattani MT, Hindmarsh PC, Brook CG, Robinson IC, Weir T, Marshall NJ (1993) Enhancement of growth hormone bioactivity by zinc in the eluted stain assay system. Endocrinology 133(6):2803–2808

    Article  PubMed  CAS  Google Scholar 

  27. McNall AD, Etherton TD, Fosmire GJ (1995) The impaired growth induced by zinc deficiency in rats is associated with decreased expression of the hepatic IGF-I and GH receptor genes. J Nutr 125(4):874–879

    PubMed  CAS  Google Scholar 

  28. Voorhees JL, Rao GV, Gordon TJ, Brooks CL (2011) Zinc binding to human lactogenic hormones and the human prolactin receptor. FEBS Lett 585(12):1783–1788

    Article  PubMed  CAS  Google Scholar 

  29. Hamza RT, Hamed AI, Sallam MT (2012) Effect of zinc supplementation on growth hormone insulin growth factor axis in short Egyptian children with zinc deficiency. Ital J Pediatr 38:21

    Article  PubMed  CAS  Google Scholar 

  30. Somm E, Bonnet N, Martinez A, Marks PM, Cadd VA et al (2012) A botulinum toxin-derived targeted secretion inhibitor downregulates the GH/IGF1 axis. J Clin Invest 122(9):3295–3306. doi:10.1172/JCI63232

    Article  PubMed  Google Scholar 

  31. Cousins RJ, Blanchard RK, Popp MP, Liu L, Cao J et al (2003) A global view of the selectivity of zinc deprivation and excess on genes expressed in human THP-1 mononuclear cells. Proc Natl Acad Sci U S A 100(12):6952–6957

    Article  PubMed  CAS  Google Scholar 

  32. Overbeck S, Uciechowski P, Ackland ML, Ford D, Rink L (2008) Intracellular zinc homeostasis in leukocyte subsets is regulated by different expression of zinc exporters ZnT-1to ZnT-9. J Leukoc Biol 83(2):368–380

    Article  PubMed  CAS  Google Scholar 

  33. Gaither LA, Eide DJ (2001) The human ZIP1 transporter mediates zinc uptake in human K562 erythroleukemia cells. J Biol Chem 276(25):22258–22264

    Article  PubMed  CAS  Google Scholar 

  34. Costello LC, Liu Y, Zou J, Franklin RB (1999) Evidence for a zinc uptake transporter in human prostate cancer cells which is regulated by prolactin and testosterone. J Biol Chem 274(25):17499–17504

    Article  PubMed  CAS  Google Scholar 

  35. Glies PJ, Cousins RJ (1982) Hormonal regulation of zinc metabolism in a human prostatic carcinoma cell line (PC-3). Cancer Res 42(1):2–7

    Google Scholar 

  36. Dufner-Beattie J, Langmade SJ, Wang F, Eide D, Andrews GK (2003) Structure, function, and regulation of a subfamily of mouse zinc transporter genes. J Biol Chem 278(50):50412–50150

    Article  Google Scholar 

  37. Gaither LA, Eide DJ (2000) Functional expression of the human hZIP2 zinc transporter. J Biol Chem 275(8):5560–5564

    Article  PubMed  CAS  Google Scholar 

  38. Cao J, Bobo JA, Liuzzi JP, Cousins RJ (2001) Effects of intracellular zinc depletion on metallothionein and ZIP2 transporter expression and apoptosis. J Leukoc Biol 70(4):559–566

    PubMed  CAS  Google Scholar 

  39. Kambe T, Geiser J, Lahner B, Salt DE, Andrews GK (2008) Slc39a1 to 3 (subfamily II) Zip genes in mice have unique cell-specific functions during adaptation to zinc deficiency. Am J Physiol Regul Integr Comp Physiol 294(5):1474–1481. doi:10.1152/ajpregu.00130.2008

    Article  Google Scholar 

  40. Xu TF, Wang XL, Yang JZ, Hu XY, Wu WF et al (2009) Overexpression of Zip-2 mRNA in the leukocytes of asthmatic infants. Pediatr Pulmonol 44(8):763–767

    Article  PubMed  Google Scholar 

  41. Ekinci D, Ceyhun SB, Aksakal E, Erdoğan O (2011) IGF and GH mRNA levels are suppressed upon exposure to micromolar concentrations of cobalt and zinc in rainbow trout white muscle. Comp Biochem Physiol C Toxicol Pharmacol 153(3):336–341. doi:10.1016/j.cbpc.2010.12.004

    Article  PubMed  Google Scholar 

  42. Taylor KM, Morgan HE, Johnson A, Hadley LJ, Nicholson RI (2003) Structure-function analysis of LIV-1, the breast cancer-associated protein that belongs to a new subfamily of zinc transporters. Biochem J 375(Pt 1):51–59

    Article  PubMed  CAS  Google Scholar 

  43. Unno J, Satoh K, Hirota M, Kanno A, Hamada S et al (2009) LIV-1 enhances the aggressive phenotype through the induction of epithelial to mesenchymal transition in human pancreatic carcinoma cells. Int J Oncol 35(4):813–821

    PubMed  CAS  Google Scholar 

  44. Zhao L, Chen W, Taylor KM, Cai B, Li X (2007) LIV-1 suppression inhibits HeLa cell invasion by targeting ERK1/2-Snail/Slug pathway. Biochem Biophys Res Commun 363(1):82–88

    Article  PubMed  CAS  Google Scholar 

  45. Lue HW, Yang X, Wang R, Qian W, Xu RZ et al (2011) LIV-1 promotes prostate cancer epithelial-to-mesenchymal transition and metastasis through HB-EGF shedding and EGFR-mediated ERK signaling. PLoS One 6(11):e27720. doi:10.1371/journal.pone.0027720

    Article  PubMed  CAS  Google Scholar 

  46. Kagara N, Tanaka N, Noguchi S, Hirano T (2007) Zinc and its transporter ZIP10 are involved in invasive behavior of breast cancer cells. Cancer Sci 98(5):692–697

    Article  PubMed  CAS  Google Scholar 

  47. Taylor KM, Hiscox S, Nicholson RI (2004) Zinc transporter LIV-1: a link between cellular development and cancer progression. Trends Endocrinol Metab 15(10):461–463

    Article  PubMed  CAS  Google Scholar 

  48. Yamashita S, Miyagi C, Fukada T, Kagara N, Che YS, Hirano T (2004) Zinc transporter LIVI controls epithelial-mesenchymal transitionin zebrafish gastrula organizer. Nature 429(6989):298–302

    Article  PubMed  CAS  Google Scholar 

  49. Kitamura H, Morikawa H, Kamon H, Lguchi M, Hojyo S et al (2006) Toll-like receptor-mediated regulation of zinc homeostasis influences dendritic cell function. Nat Immunol 7(9):971–977

    Article  PubMed  CAS  Google Scholar 

  50. Frasor J, Stossi F, Danes JM, Komm B, Lyttle CR, Katzenellenbogen BS (2004) Selective estrogen receptor modulators: discrimination of agonistic versus antagonistic activities by gene expression profiling in breast cancer cells. Cancer Res 64(4):1522–1533

    Article  PubMed  CAS  Google Scholar 

  51. Begum NA, Kobayashi M, Moriwaki Y, Matsumoto M, Toyoshima K, Seya T (2002) Mycobacterium bovis BCG cell wall and lipopolysaccharide induce a novel gene, BIGM103, encoding a 7-TM protein: identification of a new protein family having Zn-transporter and Zn-metalloprotease signatures. Genomics 80(6):630–645

    Article  PubMed  CAS  Google Scholar 

  52. He L, Girijashanker K, Dalton TP, Reed J, Li H, Soleimani M, Nebert DW (2006) ZIP8, member of the solute-carrier-39 (SLC39) metal-transporter family: characterization of transporter properties. Mol Pharmacol 70(1):171–180

    PubMed  CAS  Google Scholar 

  53. Wang CY, Jenkitkasemwong S, Duarte S, Sparkman BK, Shawki A et al (2012) ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading. J Biol Chem 287(41):34032–34043. doi:10.1074/jbc.M112.367284

    Article  PubMed  CAS  Google Scholar 

  54. Aydemir TB, Liuzzi JP, McClellan S, Cousins RJ (2009) Zinc transporter ZIP8 (SLC39A8) and zinc influence IFN-gamma expression in activated human T cells. J Leukoc Biol 86(2):337–348. doi:10.1189/jlb.1208759

    Article  PubMed  CAS  Google Scholar 

  55. Knoell DL, Liu MJ (2010) Impact of zinc metabolism on innate immune function in the setting of sepsis. Int J Vitam Nutr Res 80(4–5):271–277. doi:10.1024/0300-9831/a000034

    Article  PubMed  CAS  Google Scholar 

  56. Gálvez-Peralta M, He L, Jorge-Nebert LF, Wang B, Miller ML et al (2012) ZIP8 zinc transporter: indispensable role for both multiple-organ organogenesis and hematopoiesis in utero. PLoS One 7(5):e36055. doi:10.1371/journal.pone.0036055

    Article  PubMed  Google Scholar 

  57. Argetsinger LS, Campbell GS, Yang X, Witthuhn BA, Silvennoinen O et al (1993) Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase. Cell 74(2):237–244

    Article  PubMed  CAS  Google Scholar 

  58. Gent J, van Kerkhof P, Roza M, Bu G, Strous GJ (2002) Ligand-independent growth hormone receptor dimerization occurs in the endoplasmic reticulum and is required for ubiquitin system-dependent endocytosis. Proc Natl Acad Sci U S A 99(15):9858–9863

    Article  PubMed  CAS  Google Scholar 

  59. Waters MJ, Hoang HN, Fairlie DP, Pelekanos RA, Brown RJ (2006) New insights into growth hormone action. J Mol Endocrinol 36(1):1–7

    Article  PubMed  CAS  Google Scholar 

  60. Bruinsma JJ, Jirakulaporn T, Muslin AJ, Kornfeld K (2002) Zinc ions and cation diffusion facilitator proteins regulate ras-mediated signaling. Dev Cell 2(5):567–578

    Article  PubMed  CAS  Google Scholar 

  61. Fukada T, Hojyo S, Furuichi T (2013) Zinc signal: a new player in osteobiology. J Bone Miner Metab 31(2):129–135

    Article  PubMed  CAS  Google Scholar 

  62. Hennigar SR, Kelleher SL (2012) Zinc networks: the cell-specific compartmentalization of zinc for specialized functions. Biol Chem 393(7):565–578

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Shandong Provincial Nature Science Foundation of China (No. ZR2011HM049).

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, 44#,Wenhua Xi Road, Jinan, Shandong, 250012, China

    Ping Sun, Yali Jiang, Yanting Tao, Yuanyuan Tian, Kai Zhu & Lianying Zhang

  2. Department of Children’s Medical Laboratory Diagnosis Center, Qilu Children’s Hospital of Shandong University, Shandong, 250000, China

    Shifu Wang & Lehai Zhang

  3. Urology Department, Qilu Hospital of Shandong University, Shandong, 250012, China

    Haiyan Wan

Authors
  1. Ping Sun
    View author publications

    Search author on:PubMed Google Scholar

  2. Shifu Wang
    View author publications

    Search author on:PubMed Google Scholar

  3. Yali Jiang
    View author publications

    Search author on:PubMed Google Scholar

  4. Yanting Tao
    View author publications

    Search author on:PubMed Google Scholar

  5. Yuanyuan Tian
    View author publications

    Search author on:PubMed Google Scholar

  6. Kai Zhu
    View author publications

    Search author on:PubMed Google Scholar

  7. Haiyan Wan
    View author publications

    Search author on:PubMed Google Scholar

  8. Lehai Zhang
    View author publications

    Search author on:PubMed Google Scholar

  9. Lianying Zhang
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Lianying Zhang.

Additional information

Ping Sun and Shifu Wang contributed equally to this article

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sun, P., Wang, S., Jiang, Y. et al. Zip1, Zip2, and Zip8 mRNA Expressions Were Associated with Growth Hormone Level During the Growth Hormone Provocation Test in Children with Short Stature. Biol Trace Elem Res 155, 11–22 (2013). https://doi.org/10.1007/s12011-013-9764-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-013-9764-y

Keywords