Disease relevance of Igfbp2

• Renal biopsies from patients with diabetic nephropathy also showed markedly decreased IGFBP-2 expression when compared with patients without nephropathy [1].
• This reduction in body weight was mainly attributable to significantly (P < 0.05) lower carcass weights of CMV-IGFBP-2 transgenic vs. control mice [2].
• Therefore, we have generated transgenic mice, in which expression of a mouse IGFBP-2 complementary DNA is controlled by the cytomegalovirus (CMV) promoter [2].
• Menin also alters the structure of the chromatin surrounding the promoter of the IGFBP-2 gene, as demonstrated by the deoxyribonuclease I hypersensitivity assay [3].
• Furthermore, IGFBP-2 levels at the end of treatment correlated with residual tumor load, suggesting that IGFBP-2 might serve as an early indicator of therapeutic response [4].

High impact information on Igfbp2

• IGFBP-2, -3, -5, and -6 have heparin-binding domains and can bind glycosaminoglycans [5].
• Up-regulation of IGFBP-2 was confirmed at the protein level by Western blot analysis and validated in samples not included in the microarray analysis [6].
• IIp45, an insulin-like growth factor binding protein 2 (IGFBP-2) binding protein, antagonizes IGFBP-2 stimulation of glioma cell invasion [7].
• Thus, we report here the isolation and characterization of a gene, IIp45, whose protein product binds to IGFBP-2 and inhibits glioma cell invasion [7].
• Our previous studies have shown that insulin-like growth factor binding protein 2 (IGFBP-2) is frequently overexpressed in the highly invasive glioblastoma multiforme (GBM) [7].

Biological context of Igfbp2

• Mouse Igfbp2 and 5 colocalize to a proximal region of chromosome 1 that is syntenic with human chromosome 2q33-q36, and the two genes are 5 kb apart in a tail-to-tail orientation [8].
• These results demonstrate that up-regulation of multiple IGFBPs accompanies the absence of IGFBP-2 and that IGFBP-2 has a critical role, either directly or indirectly, in modulating spleen and liver size [9].
• To clarify the in vivo role of IGFBP-2, we have used gene targeting to introduce a null IGFBP-2 allele into the mouse genome [9].
• Here, using menin-null cells, we show that menin is essential for repression of the endogenous IGFBP-2, a gene that can regulate cell proliferation [3].
• The present study demonstrates, for the first time, the cell-specific patterns of IGF-I and -II receptor and IGFBP-2 to -6 gene expression during the processes of chondro- and osteogenesis in vivo [10].

Anatomical context of Igfbp2

• IGF-I and IGFBP-2, -3, and -4 mRNAs are detected in surrounding mesenchymal tissue, but are not detected in mesenchymal condensations or chondrocytes at any stage of development [10].
• Low insulin-like growth factor binding protein-2 expression is responsible for increased insulin receptor substrate-1 phosphorylation in mesangial cells from mice susceptible to glomerulosclerosis [1].
• IGF-I, IGF-II, and IGFBP-2, -4, -5, and -6 mRNAs are detected in osteoblasts localized in zones of endochondral ossification from E18 to at least P25 [10].
• IGFBP-2 mRNA was localized to the mouse granulosa cell, in contrast to its concentration in the rat thecal-interstitial compartment [11].
• In contrast, IGFBP-2 and -4 mRNAs were expressed predominantly in stromal cells [12].

Associations of Igfbp2 with chemical compounds

• Addition of exogenous IGFBP-2 partially blunted the effect of 25 mm glucose on IRS-1 phosphorylation in ROP MC [1].
• For IGFBP-2, dexamethasone is a potent inhibitor of secretion whilst prolactin stimulated the secretion of this binding protein into the medium [13].
• Castration-induced increases in insulin-like growth factor-binding protein 2 promotes proliferation of androgen-independent human prostate LNCaP tumors [14].
• Cortisol inhibited IGFBP-3 secretion and DNA synthesis, but increased IGFBP-2 secretion [15].
• IGFBP-2 secreting clones displayed reduced conversion of thiazolyl blue when compared to negative clones or non-transfected parental 293 cells (P < 0.01) [16].

Physical interactions of Igfbp2

• To clarify the role of insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2) in postnatal growth regulation, we crossed hemizygous CMV-IGFBP-2 transgenic mice with hemizygous PEPCK-bGH transgenic mice, which are characterized by serum GH levels in the range of 2 microgram/ml [17].

Regulatory relationships of Igfbp2

• Insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2) has been shown to inhibit IGF-dependent cell proliferation in a number of in vitro studies [2].
• Tumor suppressor menin regulates expression of insulin-like growth factor binding protein 2 [3].
• For example, IGFBP-3 and -5 mRNAs were expressed in TEBs and ducts while IGFBP-2 and -4 mRNAs were expressed in stromal cells immediately surrounding the epithelium [18].

Other interactions of Igfbp2

• RESULTS: IGF-1 and IGF binding protein 2 (IGFBP-2) mRNA were rapidly reduced whereas IGFBP-3 and IGF-R1 mRNA were increased after castration [19].
• Within the pancreas, IGFBP-2 expression was found in the islets but not in the exocrine part [2].
• 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 [12].
• Serum IGF-binding protein (IGFBP)-2 concentrations were significantly (P < 0.05) higher in I mice than in all other groups when mice were maintained on the standard diet, with a tendency to reduced IGFBP-2 concentrations in B mice [20].
• We show that there is downregulation in the expression of IGFBP-2 in the entire apical ectodermal ridge (AER) in homozygous Hd/Hd limb buds, whereas IGFBP-5 is downregulated in specific regions in the mutant AER [21].

Analytical, diagnostic and therapeutic context of Igfbp2

• Western immunoblot analysis did not reveal differences in tissue IGFBP-2 levels between B and GB mice [17].
• IGFBP-2 to -5 mRNAs were readily detectable in the developing gland by in situ hybridization analyses but were expressed in distinct cellular sites [12].
• In addition, we also found that both IGFBP-2 and HER-2 extracellular domain levels are elevated in patient sera from several cancer types, suggesting that these novel secreted biomarkers could be valuable pharmacodynamic tools in clinical trials of HSP90 inhibitors [4].
• Increased IGFBP-2 levels after castration were also identified using a human prostate tissue microarray of untreated and posthormone therapy-treated prostatectomy specimens [14].
• Moreover, further chromatin immunoprecipitation assays demonstrated that the TSS regions of the IGFBP-1 gene and those of the related IGFBP-2, -5, and -6, but not of IGFBP-3 and -4 genes, bind PPARs as well [22].

References