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Gene Review:

IGFBP4 - insulin-like growth factor binding protein 4

Ovis aries

Mazerbourg, S. et al., Choi, D. et al., Hayashi, K. et al., Gallaher, B.W. et al., Armstrong, D.G. et al., et al.

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Disease relevance of IGFBP-4

Circulating IGF-I is positively correlated with fetal weight (r = 0.66, P = 0.03), circulating IGFBP-3 (r = 0.54, P = 0.01) and IGFBP-4 (r = 0.52, P = 0.01) [1].

High impact information on IGFBP-4

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 [2].
Other heparin-binding domain-containing peptides derived from the connective tissue growth factor (CTGF) and from proteins not related to IGFBP, heparan/heparin interacting protein (HIP) and vitronectin, but not from p36 subunit of annexin II tetramer, inhibited IGFBP-4 degradation [2].
The addition of an excess of IGF-I enhanced IGFBP-4 proteolytic degradation, whereas addition of IGFBP-2 or -3 or monoclonal antibodies against IGF-I and -II dose dependently inhibited IGFBP-4 proteolytic degradation [2].
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 [2].
Follicular fluid from preovulatory follicles contains proteolytic activity degrading exogenous IGFBP-4 [2].

Biological context of IGFBP-4

IGF-binding protein-2 (IGFBP-2 mRNA was not detected until day 29 of gestation, when it appeared restricted to the dense caruncular-like stroma lining the luminal epithelium, colocalized with IGFBP-4 [3].
During follicle development, the follicular fluid content of the 39- to 42-kDa binding protein (IGFBP-3) increased, whereas that of the 34-kDa (IGFBP-2), 32-kDa, 30-kDa, and 25-kDa (IGFBP-4) binding proteins decreased [4].
The concentration of mRNA encoding IGFBP-4 increased in the follicular phase and was maintained at a significantly higher concentration during the early and mid-luteal stages (P < 0.001) [5].

Anatomical context of IGFBP-4

These data suggest that in early atretic follicles, the increase in IGFBP-2 participates in the decrease in IGFBP-4 degradation [2].
High concentrations of IGFBP-4 mRNA expression were also found in the placentome capsule [3].
The main binding proteins detected in theca cell cultures were IGFBP-4 and -2 [4].
Treatment of granulosa cells with increasing concentration of FSH resulted in decrements of up to 30% (P < .05) in the steady-state levels of IGFBP-4 transcripts [6].
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 [7].

Associations of IGFBP-4 with chemical compounds

Estradiol increased serum IGF-I, IGFBP-3, and IGFBP-4 throughout the treatment period, but it did not influence other IGFBPs in serum [8].
In fetal plasma, the circulating IGF-II/mannose-6-phosphate (M6P) receptor, IGFBP-3 and IGFBP-4 were reduced during starvation [9].
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 [9].
The concurrent provision of the C19 aromatase substrate androstenedione (10(-7) mol/L) to the culture medium from 72 hours enhanced the inhibitory effect of FSH (100 ng/mL) for a maximal decrement in IGFBP-4 transcripts of 49% (P < .05) [6].

Other interactions of IGFBP-4

Furthermore, IGFBP-3, mutated on its heparin-binding domain, was not able to inhibit IGFBP-4 proteolytic degradation [2].
Given that the biological activities of IGFs are modulated by a family of six IGF binding proteins (IGFBPs) and specific proteases, the objective was to determine the effects of age and estrogen disruption on expression of IGFs, IGFBPs and pregnancy-associated plasma protein A (PAPP-A or IGFBP-4 protease) in the ovine uterus [7].

Analytical, diagnostic and therapeutic context of IGFBP-4

Conditioned culture media were subjected to Western ligand blot before and after immunoprecipitation with a rat IGFBP-4-directed polyclonal antiserum (alpha-B104) [6].
A modest, biphasic, time-dependent response was noted for IGFBP-4 transcripts after treatment with high-dose FSH (100 ng/mL), an effect characterized by 24- and 48-hour increments (51% [P < .05] and 26% [P = .052] over untrated controls, respectively) and a 72-hour decrement (25%; P = .16) [6].

References

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]
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]
Pregnancy-specific alterations in the expression of the insulin-like growth factor system during early placental development in the ewe. Reynolds, T.S., Stevenson, K.R., Wathes, D.C. Endocrinology (1997) [Pubmed]
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]
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]
Characterization and hormonal regulation of granulosa cell-derived insulin-like growth factor binding protein-4. Choi, D., Putowski, L.T., Fielder, P.J., Rosenfeld, R.G., Rohan, R.M., Adashi, E.Y. J. Soc. Gynecol. Investig. (1996) [Pubmed]
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]
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]
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]

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