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Gene Review:

Igfbp4 - insulin-like growth factor binding protein 4

Mus musculus

Synonyms: AI875747, Band 3A, Deb2, IBP-4, IGF-binding protein 4, ...

Scharla, S.H. et al., Wang, J. et al., Zhang, M. et al., Henemyre, C. et al., Boutinaud, M. et al., et al.

Suzuki, Conover, Bale, Overgaard, Johnstone, Laursen, Füchtbauer, Oxvig, van Deursen, Boutinaud, Shand, Park, Phillips, Beattie, Flint, Allan, Ye, Price, Kassiotis, Kollias, D'Ercole, McCusker, Clemmons, Brockmann, Haley, Wolf, Karle, Kratzsch, Renne, Schwerin, Hoeflich,

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Disease relevance of Igfbp4

Overloading induced a 15% hypertrophy in soleus muscle associated with a 60% increase of IGF-I transcript levels and a doubling of IGFBP-4 mRNA levels [1].

High impact information on Igfbp4

PAPPA increases IGF bioavailability and mitogenic effectiveness in vitro through regulated cleavage of IGF-binding protein 4 (IGFBP4) [2].
Furthermore, significantly elevated serum levels of IGFBP-2, IGFBP-3, and IGFBP-4 were found in DU6i vs. DBA/2 mice [3].
It has been demonstrated that both an N-terminal and a C-terminal fragment of insulin-like growth factor-binding protein-4 exist and accumulate in the circulatory system, these fragments accounting for virtually the whole amino acid sequence of the protein [4].
Targeted expression of a protease-resistant IGFBP-4 mutant in smooth muscle of transgenic mice results in IGFBP-4 stabilization and smooth muscle hypotrophy [5].
Bladder and aortic immunoreactive IGFBP-4/transgene mRNA ratios in SMP8-BP4.7A mice were increased by 2- to 4-fold relative to SMP8-BP4 mice, indicating that the IGFBP-4.7A protein was stabilized in vivo [5].

Biological context of Igfbp4

Overexpression of IGFBP-4 was associated with SMC hypoplasia, a reciprocal phenotype to that of transgenic mice overexpressing IGF-I under control of the same promoter (SMP8-IGF-I) [6].
In the present study we have investigated the effect of TNF-alpha on the secretion of insulin-like growth factor I (IGF-I) and IGF binding protein 4 (IGFBP-4) by clonal mouse osteoblasts (MC3T3-E1 cells) using subconfluent in vitro cultures and serum-free conditions [7].
IGFBP-4 was detected in all uterine homogenates, varying in intensity throughout the estrous cycle [8].
In situ hybridization studies at metestrus and diestrus demonstrated an intense IGFBP-4 mRNA signal in antimesometrial stromal cells between the luminal epithelium and the myometrium, but at proestrus and estrus, no IGFBP-4 signal was detected [8].
This study demonstrates that ES of muscle cells in vitro not only directly modulates the gene expression of contractile proteins but also modulates proteins that are part of the IGF regulatory system, in particular IGFBP-4 [9].

Anatomical context of Igfbp4

By contrast, transgenic IGFBP-4 mRNA expression, distinguished because of a smaller transcript size, was confined to SMC-containing tissues, with the following hierarchy: bladder > aorta > stomach = uterus [6].
Effect of tumor necrosis factor-alpha on the expression of insulin-like growth factor I and insulin-like growth factor binding protein 4 in mouse osteoblasts [7].
To explore the function of the protease-resistant IGFBP-4 in vivo, expression of the mutant and native proteins was targeted to SMC of transgenic mice by means of a smooth muscle alpha-actin promoter [5].
Like primary cultures, undifferentiated 3T3-L1 cells expressed IGFBP-4 mRNA, but insignificant levels of IGF-I and IGFBP-2 mRNAs [10].
In addition, our results have identified some similarities and differences in the expression of IGFBPs between the mouse mammary epithelial cell line, HC11, and the normal mammary gland which are worthy of study, most notably the differential regulation of IGFBP-2 and the site of expression of IGFBP-4 and -6 [11].

Associations of Igfbp4 with chemical compounds

We also observed a dose-dependent inhibition of calcitriol-stimulated IGFBP-4 secretion into the culture medium (as detected by Western ligand blot), with the maximal inhibition occurring with 600 pmol/l TFN-alpha to 25 +/- 7% of control levels.(ABSTRACT TRUNCATED AT 250 WORDS)[7]
1,25-(OH)2D3 also increased IGFBP-4 (2.2 kb) transcript levels within 30 min, with the maximal stimulation of 8-fold occurring after 8 h [12].
Thyroid hormone and retinoic acid induce the synthesis of insulin-like growth factor-binding protein-4 in mouse osteoblastic cells [13].
Our data show that thyroid hormone and retinoic acid stimulate transcription of IGFBP-4 mRNA in osteoblasts, resulting in increased IGFBP-4 secretion into the medium [13].
Agents that elevate intracellular cAMP concentrations (dcAMP, forskolin, isoproterenol, and prostaglandin [PGE1]) increase secretion of IGFBP-4 and IGFBP-5 from L6 cells [14].

Regulatory relationships of Igfbp4

The presence of TNF-alpha (600 pmol/l) inhibited this calcitriol-induced stimulation of IGFBP-4 mRNA levels from 4 h onwards, with complete inhibition of the calcitriol effect occurring at 24 h [7].
Real-time RT-PCR analysis determined that pretreatment with IGF-binding protein-4 did not block GH-induced Tbx3 expression in vitro [15].
We postulate that the increase in the 50-kDa IGF pool might enhance IGFs bioavailability via a mechanism involving IGFBP-4-specific protease [16].

Other interactions of Igfbp4

Mice homozygous for targeted defects in IGFBP-3, -4, and -5 remain viable and at birth were the same size as IGFBP-4 KO mice [17].
Because basal secretion of IGFBPs is very low in MC3T3-E1 cells, effects of TNF-alpha on IGFBP secretion were studied in cultures in which IGFBP-4 expression was increased by calcitriol (1,25(OH)2D3) treatment [7].
Expression of insulin-like growth factor binding protein-4, insulin-like growth factor-I receptor, and insulin-like growth factor-I in the mouse uterus throughout the estrous cycle [8].
IGFBP-2 mRNA was localized to restricted sites in the neck of the TEB and along the ductal structures, whereas IGFBP-4 mRNA was widely expressed in the stroma surrounding the epithelial structures [18].
Postnatally, IGFBP-4 was substituted by IGFBP-5 in the same region [19].

Analytical, diagnostic and therapeutic context of Igfbp4

The abundance of IGFBP-4 measured by Western ligand blotting or by immunoblotting, was 8- to 10-fold higher in aorta and bladder of SMP8-BP-4 mice than in their nontransgenic littermates, with no change in plasma IGFBP-4 levels [6].
Of the IGFBPs studied the abundance of IGFBP-3 and IGFBP-4 was increased by 2-3.7-fold, and the abundance of IGFBP-5 was decreased by approximately 3-fold (as judged by Western immunoblot analysis) [20].
Immunoprecipitation of solubilized crude membranes indicated that the 31 kDa protein was membrane associated IGFBP-4 [21].

References

Regulation of IGF-I, IGFBP-4 and IGFBP-5 gene expression by loading in mouse skeletal muscle. Awede, B., Thissen, J., Gailly, P., Lebacq, J. FEBS Lett. (1999) [Pubmed]
Metalloproteinase pregnancy-associated plasma protein A is a critical growth regulatory factor during fetal development. Conover, C.A., Bale, L.K., Overgaard, M.T., Johnstone, E.W., Laursen, U.H., Füchtbauer, E.M., Oxvig, C., van Deursen, J. Development (2004) [Pubmed]
Genome-wide search for loci controlling serum IGF binding protein levels of mice. Brockmann, G.A., Haley, C.S., Wolf, E., Karle, S., Kratzsch, J., Renne, U., Schwerin, M., Hoeflich, A. FASEB J. (2001) [Pubmed]
Synthesis of the blood circulating C-terminal fragment of insulin-like growth factor (IGF)-binding protein-4 in its native conformation. Crystallization, heparin and IGF binding, and osteogenic activity. Fernández-Tornero, C., Lozano, R.M., Rivas, G., Jiménez, M.A., Ständker, L., Díaz-Gonzalez, D., Forssmann, W.G., Cuevas, P., Romero, A., Giménez-Gallego, G. J. Biol. Chem. (2005) [Pubmed]
Targeted expression of a protease-resistant IGFBP-4 mutant in smooth muscle of transgenic mice results in IGFBP-4 stabilization and smooth muscle hypotrophy. Zhang, M., Smith, E.P., Kuroda, H., Banach, W., Chernausek, S.D., Fagin, J.A. J. Biol. Chem. (2002) [Pubmed]
Overexpression of insulin-like growth factor-binding protein-4 (IGFBP-4) in smooth muscle cells of transgenic mice through a smooth muscle alpha-actin-IGFBP-4 fusion gene induces smooth muscle hypoplasia. Wang, J., Niu, W., Witte, D.P., Chernausek, S.D., Nikiforov, Y.E., Clemens, T.L., Sharifi, B., Strauch, A.R., Fagin, J.A. Endocrinology (1998) [Pubmed]
Effect of tumor necrosis factor-alpha on the expression of insulin-like growth factor I and insulin-like growth factor binding protein 4 in mouse osteoblasts. Scharla, S.H., Strong, D.D., Mohan, S., Chevalley, T., Linkhart, T.A. Eur. J. Endocrinol. (1994) [Pubmed]
Expression of insulin-like growth factor binding protein-4, insulin-like growth factor-I receptor, and insulin-like growth factor-I in the mouse uterus throughout the estrous cycle. Henemyre, C., Markoff, E. Mol. Reprod. Dev. (1999) [Pubmed]
Electrical stimulation modulates IGF binding protein transcript levels in C2C12 myotubes. Bayol, S., Brownson, C., Loughna, P.T. Cell Biochem. Funct. (2005) [Pubmed]
Expression of insulin-like growth factor-I (IGF-I) and IGF-binding proteins during adipogenesis. Boney, C.M., Moats-Staats, B.M., Stiles, A.D., D'Ercole, A.J. Endocrinology (1994) [Pubmed]
A quantitative RT-PCR study of the mRNA expression profile of the IGF axis during mammary gland development. Boutinaud, M., Shand, J.H., Park, M.A., Phillips, K., Beattie, J., Flint, D.J., Allan, G.J. J. Mol. Endocrinol. (2004) [Pubmed]
1,25-Dihydroxyvitamin D3 differentially regulates the production of insulin-like growth factor I (IGF-I) and IGF-binding protein-4 in mouse osteoblasts. Scharla, S.H., Strong, D.D., Mohan, S., Baylink, D.J., Linkhart, T.A. Endocrinology (1991) [Pubmed]
Thyroid hormone and retinoic acid induce the synthesis of insulin-like growth factor-binding protein-4 in mouse osteoblastic cells. Glantschnig, H., Varga, F., Klaushofer, K. Endocrinology (1996) [Pubmed]
Role for cyclic adenosine monophosphate in modulating insulin-like growth factor binding protein secretion by muscle cells. McCusker, R.H., Clemmons, D.R. J. Cell. Physiol. (1998) [Pubmed]
Whole genome microarray analysis of growth hormone-induced gene expression in bone: T-box3, a novel transcription factor, regulates osteoblast proliferation. Govoni, K.E., Lee, S.K., Chadwick, R.B., Yu, H., Kasukawa, Y., Baylink, D.J., Mohan, S. Am. J. Physiol. Endocrinol. Metab. (2006) [Pubmed]
Effects of recombinant insulin-like growth factor-binding protein-4 on bone formation parameters in mice. Miyakoshi, N., Richman, C., Qin, X., Baylink, D.J., Mohan, S. Endocrinology (1999) [Pubmed]
Diminished growth and enhanced glucose metabolism in triple knockout mice containing mutations of insulin-like growth factor binding protein-3, -4, and -5. Ning, Y., Schuller, A.G., Bradshaw, S., Rotwein, P., Ludwig, T., Frystyk, J., Pintar, J.E. Mol. Endocrinol. (2006) [Pubmed]
Expression of the insulin-like growth factor binding proteins during postnatal development of the murine mammary gland. Allar, M.A., Wood, T.L. Endocrinology (2004) [Pubmed]
Expression of IGFBPs in the developing mouse submandibular and von Ebner's glands. Suzuki, Y. Anat. Embryol. (2006) [Pubmed]
Tumor necrosis factor-alpha regulation of insulin-like growth factor-I, type 1 IGF receptor, and IGF binding protein expression in cerebellum of transgenic mice. Ye, P., Price, W., Kassiotis, G., Kollias, G., D'Ercole, A.J. J. Neurosci. Res. (2003) [Pubmed]
Characterization of the insulin-like growth factors (IGF) axis in a cultured mouse Leydig cell line (TM-3). Hasegawa, T., Cohen, P., Hasegawa, Y., Fielder, P.J., Rosenfeld, R.G. Growth Regul. (1995) [Pubmed]

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