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Gene Review

IGFBP-3  -  insulin-like growth factor binding protein 3

Ovis aries

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Disease relevance of IGFBP-3


High impact information on IGFBP-3

  • As an independent confirmation of this interaction, using a yeast two-hybrid system, we cloned Tf from a human liver complementary DNA library as an IGFBP-3 protein partner [5].
  • Plasma IGFBP-2 content was significantly reduced in prenatal T-treated newborns, but by 4 months these females had significantly higher circulating IGF-I and IGFBP-3 concentrations and faster growth rates than control females [1].
  • There was a transient increase in plasma IGF-I and IGFBP-3 concentrations at fetal 90 d in prenatal T-treated fetuses [1].
  • C-terminal, but not N-terminal, proteolytic fragments derived from IGFBP-3 (aa 161-264), as well as heparin-binding domain-containing peptides derived from the C-terminal domain of IGFBP-3 and -5 also induced the inhibition of IGFBP-4 proteolytic degradation [6].
  • Furthermore, IGFBP-3, mutated on its heparin-binding domain, was not able to inhibit IGFBP-4 proteolytic degradation [6].

Biological context of IGFBP-3

  • To determine if there was any difference in plasma IGF-I and IGFBP-3 concentrations in growth-retarded fetal sheep with altered renal status, concentrations were measured by specific radioimmunoassay from bilaterally nephrectomized fetal sheep between Days 113 and 135 gestation [7].
  • IGFBP-3 was the major postnatal binding protein, while in the fetus IGFBP-2, IGFBP-3 and the circulating IGF type 2 receptor fragment each contributed 25-30% of total IGF binding capacity [8].
  • There was no change in plasma IGFBP-3 concentration with gestational age in either experimental group [7].
  • Neither insulin nor rhIGF-I treatment had an effect on hepatic IGFBP-3 gene expression [9].
  • The different affinities of des(1-3)IGF-I for IGFBP-3, -2, and -1 lead us to suggest that IGFBP-2 and/or -1 are present in the deep stroma and glands, whereas IGFBP-3 may be responsible for the additional binding sites in the myometrium and blood vessel walls [10].

Anatomical context of IGFBP-3


Associations of IGFBP-3 with chemical compounds

  • Ethanol exposure did not alter maternal or fetal plasma concentrations of IGFBP-2 and IGFBP-3, measured by Western ligand blotting [16].
  • Estradiol increased serum IGF-I, IGFBP-3, and IGFBP-4 throughout the treatment period, but it did not influence other IGFBPs in serum [17].
  • While circulating IGF-II/M6P receptor and IGFBP-4 levels were increased following the fetal insulin or glucose infusion, IGFBP-3 was unchanged and increased only after 48 h of maternal refeeding [18].
  • In fetal plasma, the circulating IGF-II/mannose-6-phosphate (M6P) receptor, IGFBP-3 and IGFBP-4 were reduced during starvation [18].
  • On PNDs 14 and 56, IGFBP-3 mRNA was decreased in the uterus of EV-treated ewes, but IGF-1R and IGFBP-4 mRNAs were not affected [19].

Physical interactions of IGFBP-3

  • This inhibition might be partly mediated by direct interaction of IGFBP-4 proteinase(s) and heparin-binding domain within the C-terminal region from IGFBP-3 and -5 [6].
  • Serial blood samples were taken at 15-min intervals for 12 h for the determination of GH and IGF-I content by radioimmunoassay and for IGF-binding protein-3 (IGFBP-3) levels by Western blotting [20].

Regulatory relationships of IGFBP-3

  • IGFBP-2 was suppressed (P less than 0.05) by day 55 and IGFBP-3 and 4 did not change [21].

Other interactions of IGFBP-3

  • These data show that each of the IGF carrier proteins is sensitive of changes in nutrition, either acutely, such as IGFBP-1, or chronically, as for IGFBP-3 [18].
  • The co-ordinate maximum expression of mRNA for both IGF-I and IGF-II, the type 1 IGF receptor and IGFBP-3 during the period when the gametes and embryo are in transit suggests a role for IGF-I and possibly IGF-II peptides in providing an oviductal environment propitious to conception and early embryonic growth and metabolism [22].
  • No difference was found in IGF-1, IGF-2 or IGFBP-3 levels between the NR and C groups at either gestational age [23].
  • A possible role of IGFBP-3 proteolysis in the ovine ULF may be to selectively increase the bioavailability of IGF-1 in the uterine microenvironment, which may be crucial for the rapid elongation of trophoblast that begins during days 12-15 after mating [24].

Analytical, diagnostic and therapeutic context of IGFBP-3


  1. Prenatal exposure to excess testosterone modifies the developmental trajectory of the insulin-like growth factor system in female sheep. Crespi, E.J., Steckler, T.L., Mohankumar, P.S., Padmanabhan, V. J. Physiol. (Lond.) (2006) [Pubmed]
  2. Circulating insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs) and tissue mRNA levels of IGFBP-2 and IGFBP-4 in the ovine fetus. Carr, J.M., Owens, J.A., Grant, P.A., Walton, P.E., Owens, P.C., Wallace, J.C. J. Endocrinol. (1995) [Pubmed]
  3. Decreased serum insulin-like growth factor-I associated with growth failure in newborn lambs with experimental cyanotic heart disease. Bernstein, D., Jasper, J.R., Rosenfeld, R.G., Hintz, R.L. J. Clin. Invest. (1992) [Pubmed]
  4. Fetal programming of insulin-like growth factor (IGF)-I and IGF-binding protein-3: evidence for an altered response to undernutrition in late gestation following exposure to periconceptual undernutrition in the sheep. Gallaher, B.W., Breier, B.H., Keven, C.L., Harding, J.E., Gluckman, P.D. J. Endocrinol. (1998) [Pubmed]
  5. Transferrin is an insulin-like growth factor-binding protein-3 binding protein. Weinzimer, S.A., Gibson, T.B., Collett-Solberg, P.F., Khare, A., Liu, B., Cohen, P. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  6. Insulin-like growth factor binding protein-4 proteolytic degradation in ovine preovulatory follicles: studies of underlying mechanisms. Mazerbourg, S., Zapf, J., Bar, R.S., Brigstock, D.R., Lalou, C., Binoux, M., Monget, P. Endocrinology (1999) [Pubmed]
  7. Fetal plasma insulin-like growth factor-binding protein-3 concentrations are elevated following bilateral nephrectomy in fetal sheep. Beanland, C., Browne, C., Young, R., Owens, J., Walton, P., Thorburn, G. Reprod. Fertil. Dev. (1995) [Pubmed]
  8. Ontogenic differences in the nutritional regulation of circulating IGF binding proteins in sheep plasma. Gallaher, B.W., Breier, B.H., Oliver, M.H., Harding, J.E., Gluckman, P.D. Acta Endocrinol. (1992) [Pubmed]
  9. Effects of intravenous insulin-like growth factor-I and insulin administration on insulin-like growth factor-binding proteins in the ovine fetus. Shen, W.H., Yang, X., Boyle, D.W., Lee, W.H., Liechty, E.A. J. Endocrinol. (2001) [Pubmed]
  10. Localization of insulin-like growth factor-I (IGF-I) and -II messenger ribonucleic acid and type 1 IGF receptors in the ovine uterus during the estrous cycle and early pregnancy. Stevenson, K.R., Gilmour, R.S., Wathes, D.C. Endocrinology (1994) [Pubmed]
  11. Effect of maternal body condition on placental and fetal growth and the insulin-like growth factor axis in Dorset ewes. Osgerby, J.C., Gadd, T.S., Wathes, D.C. Reproduction (2003) [Pubmed]
  12. Insulin-like growth factor (IGF)-binding protein production by primary cultures of ovine granulosa and theca cells. The effects of IGF-I, gonadotropin, and follicle size. Armstrong, D.G., Hogg, C.O., Campbell, B.K., Webb, R. Biol. Reprod. (1996) [Pubmed]
  13. Phorbol esters showing selective activation of PKC isozymes in vitro regulate thyroid function and insulin-like growth factor binding protein secretion. Eggo, M.C., Sheppard, M.C., Evans, F.J., Lord, J.M. Cell. Signal. (1994) [Pubmed]
  14. Effect of a high maternal dietary intake during mid-gestation on components of the utero-placental insulin-like growth factor (IGF) system in adolescent sheep with retarded placental development. Gadd, T.S., Aitken, R.P., Wallace, J.M., Wathes, D.C. J. Reprod. Fertil. (2000) [Pubmed]
  15. The effects of maternal nutrition and body condition on placental and foetal growth in the ewe. Osgerby, J.C., Gadd, T.S., Wathes, D.C. Placenta (2003) [Pubmed]
  16. Acute ethanol exposure in pregnancy alters the insulin-like growth factor axis of fetal and maternal sheep. Gatford, K.L., Dalitz, P.A., Cock, M.L., Harding, R., Owens, J.A. Am. J. Physiol. Endocrinol. Metab. (2007) [Pubmed]
  17. Estradiol increases relative amounts of insulin-like growth factor binding protein (IGFBP)-3 in serum and expression of IGFBP-2 in anterior pituitaries of ewes. Clapper, J.A., Snyder, J.L., Roberts, A.J., Hamernik, D.L., Moss, G.E. Biol. Reprod. (1998) [Pubmed]
  18. Circulating insulin-like growth factor II/mannose-6-phosphate receptor and insulin-like growth factor binding proteins in fetal sheep plasma are regulated by glucose and insulin. Gallaher, B.W., Oliver, M.H., Eichhorn, K., Kessler, U., Kiess, W., Harding, J.E., Gluckman, P.D., Breier, B.H. Eur. J. Endocrinol. (1994) [Pubmed]
  19. The IGF system in the neonatal ovine uterus. Hayashi, K., Carpenter, K.D., Welsh, T.H., Burghardt, R.C., Spicer, L.J., Spencer, T.E. Reproduction (2005) [Pubmed]
  20. Effect of high-protein feed supplements on concentrations of growth hormone (GH), insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 in plasma and on the amounts of GH and messenger RNA for GH in the pituitary glands of adult rams. Clarke, I.J., Fletcher, T.P., Pomares, C.C., Holmes, J.H., Dunshea, F., Thomas, G.B., Tilbrook, A.J., Walton, P.E., Galloway, D.B. J. Endocrinol. (1993) [Pubmed]
  21. Body growth, carcass composition, and endocrine changes in lambs chronically treated with recombinantly derived insulin-like growth factor-I. Cottam, Y.H., Blair, H.T., Gallaher, B.W., Purchas, R.W., Breier, B.H., McCutcheon, S.N., Gluckman, P.D. Endocrinology (1992) [Pubmed]
  22. Insulin-like growth factors and their binding proteins in the ovine oviduct during the oestrous cycle. Stevenson, K.R., Wathes, D.C. J. Reprod. Fertil. (1996) [Pubmed]
  23. Maternal nutrient restriction during early to mid gestation up-regulates cardiac insulin-like growth factor (IGF) receptors associated with enlarged ventricular size in fetal sheep. Dong, F., Ford, S.P., Fang, C.X., Nijland, M.J., Nathanielsz, P.W., Ren, J. Growth Horm. IGF Res. (2005) [Pubmed]
  24. The proteolysis of insulin-like growth factor binding proteins in ovine uterine luminal fluid. Peterson, A.J., Ledgard, A.M., Hodgkinson, S.C. Reprod. Fertil. Dev. (1998) [Pubmed]
  25. Oestrogen regulation of insulin-like growth factor binding protein-3 (IGFBP-3) and expression of IGFBP-3 messenger RNA in the ovine endometrium. Peterson, A.J., Ledgard, A.M., Hodgkinson, S.C. Reprod. Fertil. Dev. (1998) [Pubmed]
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