Disease relevance of IGFBP4

• Insulin-like growth factor binding protein 4 (IGFBP4/BP4) gene expression plays an important role in the transition from proliferation to differentiation of a human colon cancer cell line, CaCo2 [1].
• In this study we report the preparation of a human osteosarcoma cell cDNA library and describe the isolation and sequence determination of a clone encoding the complete sequence of a novel human insulin-like growth factor (IGF)-binding protein (hIGFBP-4) [2].
• Effects of chronic renal failure and growth hormone on serum levels of insulin-like growth factor-binding protein-4 (IGFBP-4) and IGFBP-5 in children: a report of the Southwest Pediatric Nephrology Study Group [3].
• To investigate the role of IGFBP-4 in the physiology of the IGF system, we developed a sensitive RIA for IGFBP-4 employing, as antigen, tracer, and standard, recombinant human IGFBP-4 (rhIGFBP-4) expressed in Escherichia coli as a fusion protein with glutathione S-transferase and affinity purified with glutathione-derivatized resin [4].
• Insulin-like growth factor-I (IGF-I) regulates IGFBP-3 and IGFBP-4 by multiple mechanisms in A549 human adenocarcinoma cells [5].

High impact information on IGFBP4

• IGFBP-2 and IGFBP-4 are secreted primarily into the basolateral side (71 and 87%, respectively), whereas IGFBP-6 is targeted to the apical surface (76%) as a possible consequence of an active sorting [6].
• Estrogen receptor expression was positively correlated with BP-2 (Spearman correlation coefficient, rs = .262; P = .0001), BP-4 (rs = .313; P = .0001), and BP-5 (rs = .242; P = .0002) [7].
• RESULTS: Binding protein (BP)-2, BP-3, BP-4, and BP-5 were identified in breast cancer extracts [7].
• IMPLICATIONS: These data suggest that the IGFBPs may play a role in breast cancer biology and that BP-4 levels, analyzed in conjunction with tumor size, may have prognostic significance [7].
• BP-4 was weakly inversely correlated with tumor size (rs = -.141; P = .0295) and S-phase fraction (rs = -.216; P = .0025) [7].

Chemical compound and disease context of IGFBP4

• Agents that increase cAMP including forskolin, (Bu)2cAMP, isobutyl-methylxanthine, and histamine increased IGFBP-4 and IGFBP-4 messenger RNA in BPE-1 cells 2- to 5-fold and 2- to 3-fold, respectively, similar to results previously reported in human osteosarcoma cells and fibroblasts [8].
• Retinoic acid stimulates IGF binding protein (IGFBP)-6 and depresses IGFBP-2 and IGFBP-4 in SK-N-SH human neuroblastoma cells [9].
• In all the neural cells tested (B104s, C6 astrocytoma, primary neonatal astrocytes and primary fetal neurons), IGFBP-4 was definitively identified by immunoblotting [10].
• 1,25-(OH)2D3 also increased IGFBP-4 expression in skin fibroblasts but not in hepatocellular carcinoma cells [11].
• HOBIT cells, but not the osteosarcoma cell lines, appeared to produce a cycloheximide-sensitive inhibitor of the IGFBP-4 proteolytic reaction [12].

Biological context of IGFBP4

• By linkage analysis, IGFBP4 maps to the chromosome 17q interval THRA1-D17S579 [13].
• 1. We have developed a CA-repeat polymorphism from a cosmid clone containing IGFBP4 [13].
• By fluorescent in situ hybridization to metaphase chromosomes, the IGFBP4 gene was then localized to chromosomal region 17q21-21 [14].
• These findings indicate that interferon-gamma may indirectly modulate bone formation via the the release of tumour-derived IGFBP4. suggesting that the immune system may influence bone turnover in MM [15].
• In a transient transfection study, IE2-mediated repression of a reporter driven either by a synthetic promoter containing the IGFBP4 TATA/IBS element or by the native IGFBP4 promoter was dependent on the intactness of the IBS [16].

Anatomical context of IGFBP4

• IGFBP4 mRNA was also localized in endothelium, but in addition was present in stromal connective tissue and in GC of the one Graafian follicle detected in this study, but not consistently in atretic follicles [17].
• The present study demonstrates that the human MM cell line, ARH-77, expresses IGFBP4 and, to a lesser extent, IGFBP6 mRNA and protein [15].
• IGFBP4 expression in myeloma cells may be modulated by cytokines released by stromal cells and T cells in the microenvironment [15].
• The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A [18].
• HT29 cells also produce two other isoforms (28 and 31 kDa, nonreduced) of the HT29-IGFBP having the same partial NH2-terminal amino acid sequence as the 27-kDa protein [19].

Associations of IGFBP4 with chemical compounds

• In retinal and glomerular EC the IGFBP4/IGFBP5 ratio controls the response of these cells to IGF-I and high levels of glucose, in terms of cellular growth [20].
• The effects of IGFs on IGFBP-4 levels in this cell-free system were time, temperature, and pH dependent and were prevented by the serine proteinase inhibitor, aprotinin, by the divalent cation chelator, EDTA, and by the metal ion chelator, 1,10-phenanthroline [21].
• In addition, when medium from IGF-I-treated cells was incubated with rat IGFBP-4, the decrease in IGFBP-4 was inhibited by chelators of divalent cations and inhibitors of serine proteases [22].
• Pregnancy-associated plasma protein-a is the insulin-like growth factor binding protein-4 protease secreted by human ovarian granulosa cells and is a marker of dominant follicle selection and the corpus luteum [23].
• Cyclic adenosine monophosphate stimulates insulin-like growth factor binding protein-4 and its messenger ribonucleic acid in a clonal endothelial cell line [8].

Physical interactions of IGFBP4

• Microarray analysis of implantation and explantation samples of recovery patients further revealed elevated IGF-II and IGF binding proteins IGFBP4 and IGFBP6 [24].
• Pregnancy-associated plasma protein-A accounts for the insulin-like growth factor (IGF)-binding protein-4 (IGFBP-4) proteolytic activity in human pregnancy serum and enhances the mitogenic activity of IGF by degrading IGFBP-4 in vitro [25].
• Western ligand blotting with 125I-IGF II under nonreducing conditions of recombinant human (rh) IGFBP-containing yeast lysates revealed specific binding bands for IGFBP-4, -5, and -6 at apparent molecular masses of 24-26, 30-32, and 24-26 kDa, respectively, indicating processing of the fusion proteins [26].
• Effects of estrogen and parathyroid hormone on osteoblastic activity via regulating the binding activity of insulin-like growth factor binding protein-4 in SaOS-2 cells: implications for the pathogenesis of postmenopausal osteoporosis [27].

Enzymatic interactions of IGFBP4

• This IGF-regulated loss of IGFBP-4 was inhibited by metalloproteinase inhibitors and appeared to be due to a proteinase that cleaved IGFBP-4 in 18 and 14 kD fragments identified by western immunoblotting [28].
• Herein, we first determined that PAPP-A cleaves IGFBP-4 at a single site (Met-135/Lys-136), and we analysed the influence of ionic strength, pH and zinc ion concentration on the cleavage reaction [29].

Co-localisations of IGFBP4

• Two main forms of IGFBPs were released, IGFBP-3 and a 24-kDa form which comigrated with serum IGFBP-4 [30].

Regulatory relationships of IGFBP4

• Both IGF-I and IGF-II were capable of inducing a decrease in IGFBP-4; however, IGF-II was more effective [28].
• Insulin-like growth factors (IGFs) reduce IGF-binding protein-4 (IGFBP-4) concentration and stimulate IGFBP-3 independently of IGF receptors in human fibroblasts and epidermal cells [31].
• Proteolysis of radiolabeled IGFBP-4 in conditioned media from OSE(tsT) lines was IGF-dependent and blocked by anti-PAPP-A antisera [32].
• However, administration of epidermal growth factor (EGF) induced polarized secretion of IGFBP-4 by increasing secretion from the apical surface more than from the basolateral aspect [33].
• All of the IGFBPs, except the TGF-beta1-regulated IGFBP-4, were modulated at mRNA level [34].
• We find that PAPP-A-mediated IGF-dependent cleavage of IGFBP-4 is inhibited by IGFBP-5, which sequesters IGF from IGFBP-4, and that cleavage of both IGFBP-4 and -5 is required for the release of bioactive IGF [35].

Other interactions of IGFBP4

• RESULTS: MCF-7 cells expressed IGFBP-2, IGFBP-4, and IGFBP-5 RNA and protein [36].
• This IGFBP (HT29-IGFBP) has been characterized by performing ligand blotting and competitive binding experiments [19].
• When the six characterized IGFBP were added to hOB-CM, only IGFBP-4 disappeared in response to IGF-II addition [28].
• IGFBP4 changes were inversely correlated with IGF-1 variations [37].
• IGFBP-4 and IGFBP-5 mRNA were expressed additionally in low abundance in the chorionic mesoderm [38].

Analytical, diagnostic and therapeutic context of IGFBP4

• Molecular cloning of mouse insulin-like growth factor binding protein 4 (IGFBP4) cDNA and expression of a fusion protein with IGF-binding activity [39].
• Sequence determination revealed that hIGFBP-4 is a unique gene product with significant amino- and carboxy-terminal sequence similarity to three other known IGFBPs [2].
• Recombinant synthesis of insulin-like growth factor-binding protein-4 (IGFBP-4): Development, validation, and application of a radioimmunoassay for IGFBP-4 in human serum and other biological fluids [4].
• A 24-kilodalton (kDa) IGF-binding protein (IGFBP) secreted by stromal cells was identified as IGFBP-4 by immunoprecipitation and Western ligand blotting [21].
• IGFBP-4 was barely detectable by Western ligand blotting in PF, and levels of IGFBP-1, determined by immunoassay, were not appreciably different in PF and serum [40].

References