Disease relevance of Igf2

• The SHR.BN-D1Mit3/Igf2 congenic strain represents an important new model for fine mapping and characterization of genes on chromosome 1 involved in the pathogenesis of spontaneous hypertension [1].
• Alterations of the M6p/Igf2 receptor gene in hepatocellular carcinomas induced by N-nitrosodiethylamine and a choline-deficient L-amino acid-defined diet in rats [2].
• Alterations of the M6p/Igf2 receptor gene in lung adenocarcinomas induced by N-nitrosobis(2-hydroxypropyl)amine in rats [3].
• This is to our knowledge the first study correlating the increase in post-implantation embryo loss obtained after paternal drug treatment with the decrease in the expression of Igf2 in these embryos [4].
• CONCLUSIONS: The present study suggests an association between the emergence of autoimmune diabetes and a defect in Igf2 expression in the thymus of BBDP rats [5].

High impact information on Igf2

• Proliferation of Buffalo rat liver cells in serum-free medium does not depend upon multiplication-stimulating activity (MSA) [6].
• The absence of MSA in the 3A2 and 61t media was not due to inactivation of MSA by these two cell lines [6].
• A line of Buffalo rat liver cells (BRL 3A) that multiplies in the absence of serum produces a family of polypeptides termed MSA that can partially satisfy the serum requirement for growth of chick embryo fibroblasts [6].
• IGF-I appears to mediate the effects of growth hormone on cartilage to promote skeletal growth whereas IGF-II may have a special role in fetal development and in the central nervous system [7].
• Insulin-like growth factor-I (IGF-I) and IGF-II are mitogenic polypeptides of relative molecular mass (Mr) approximately 7,500 isolated from human plasma each containing four peptide domains in a single chain and identical at more than 60% of their amino acid loci [7].

Chemical compound and disease context of Igf2

• An insulin-like growth factor II (IGF-II) receptor was purified from rat chondrosarcoma cells by Triton X-100 solubilization of a 100,000 X g membrane preparation and affinity chromatography on a multiplication-stimulating activity (MSA)-Sepharose column [8].
• Body weight, blood glucose, plasma insulin, TSH and GH and pituitary GH content, as well as serum IGF-I, IGF-II, IGFBP-1, -2 and -3 and their liver mRNA expression were assayed [9].
• Subcutaneous infusion of IGF-I or IGF-II, but not vehicle, halted (P < 0.01) the progression of hyperalgesia in streptozotocin-diabetic rats [10].
• Anti-IGF-II antibody inhibits the cardiomyocyte hypertrophy induced by anti-IGF-I and anti-IGF-IR antibodies or by genistein [11].
• At the same level of DOCA-salt hypertension, the SHR.BN-D1Mit3/Igf2 congenic strain showed significantly greater proteinuria and histologically assessed renal vascular and glomerular injury than the SHR progenitor strain [12].

Biological context of Igf2

• To investigate this possibility, we replaced a region of chromosome 1 in the SHR (defined by the markers D1Mit3 and Igf2) with the corresponding chromosome segment from the normotensive Brown-Norway (BN) strain [1].
• Polymerase chain reaction genotyping using 60 polymorphic microsatellite markers dispersed throughout the genome confirmed the congenic status of the new strain designated SHR.BN-D1Mit3/Igf2 [1].
• Since Igf2 is an imprinted gene and the imprint mark is established during spermatogenesis, the present study suggests that paternal tamoxifen treatment may have affected imprinting of the gene during spermatogenesis thereby decreasing its expression and leading to increase in POL [4].
• The disruption of Ctcf, which encodes a repressor of Igf2, was associated with enhanced Igf2 gene expression [13].
• In addition, Ctcf disruption and forced Igf2 expression both enabled cells to proliferate in soft agar, a phenotype associated with malignant growth in vivo [13].

Anatomical context of Igf2

• To investigate the in vivo role of IGF-II, we have studied IGF-II biosynthesis in the BRL-3A rat liver cell line [7].
• Multiplication-stimulating activity (MSA) stimulates the uptake of xylose and alpha-aminoisobutyric acid (AIB) by intact rat soleus muscle [14].
• The insulin-like growth factor, multiplication stimulating activity (MSA), and insulin were recently shown to stimulate proteoglycan synthesis in monolayer cultures of chondrocytes derived from the Swarm rat chondrosarcoma [15].
• We now demonstrate that fibroblasts derived from rat embryos (REFs) have specific MSA receptors and respond to MSA with increased DNA synthesis [16].
• Thus, in addition to modulating the stimulation of growth and differentiation by IGF-II in fetal tissues, rIGFBP-2 may play a homeostatic role during catabolic states in the adult rat [17].

Associations of Igf2 with chemical compounds

• In contrast, MSA only displaced 16% of the 125I-labeling of the insulin receptor when it maximally stimulates the uptake of xylose and AIB, indicating that the insulin receptor is not primarily involved in mediating these effects [14].
• When 125I-MSA was chemically cross-linked to the purified receptor and analyzed by sodium dodecyl sulfate-gel electrophoresis (with and without dithiothreitol) and autoradiography, the radioactive bands coincided with the Mr = 210,000 and 250,000 bands identified by silver staining [8].
• Two apparent peaks of IGF-II/mannose-6-phosphate receptor mRNA levels were seen, on day 20 and between days 50-80 [18].
• Dexamethasone treatment of 4-day-old rats for 4 days caused a greater (90%) decrease in hepatic IGF-II mRNA than in rIGFBP-2 mRNA (50%), suggesting subtle differences in the developmental regulation of the two mRNAs [17].
• The role of insulin-like growth factor binding proteins (IGFBPs) in regulation by IGF-II of glycogenesis and DNA synthesis was investigated in hepatocytes isolated from fetal rat livers at days 15 and 18 of gestation and grown in the presence or absence of cortisol [19].

Physical interactions of Igf2

• A serum somatomedin-binding protein was found to interfere in the radioimmunoassay by competing with antibody for binding 125I-labeled MSA [20].
• In the CSF, transported IGF-II is complexed to IGFBP-2 and essentially demonstrates an endocrine mode of action with a balance of locally produced IGFBPs modulating its bioactivity in the wound [21].
• Competitive binding analysis performed on choroid plexus IGFBP showed preferential high affinity binding for IGF-II compared with that for IGF-I [22].
• IGFBP-6 binds IGF II with high affinity and prevents IGF II-mediated effects [23].
• Additional studies with latent TGF-beta 1 isolated from platelets indicated that this material could also bind to the isolated IGF-II/man6P receptor [24].

Regulatory relationships of Igf2

• IGF-II action is negatively regulated by IGFBP-1 whose synthesis increases in the presence of glucocorticoids [19].
• Later in the wounding response, levels of IGF-II decline in the CSF and the wound neuropil, possibly with the aid of increased IGFBP-5 levels that may help to locally sequester and down-regulate IGF-II activity [21].
• We generated transgenic mice (C57BL6/SJL) expressing IGF-II in beta cells under control of the rat Insulin I promoter in order to study the role of islet hyperplasia and hyperinsulinemia in the development of type 2 diabetes [25].
• [3H]Thymidine incorporation in the presence of epidermal growth factor (50 ng/ml) was stimulated 66% by IGF-II (300 ng/ml) in control cells compared with 220% in cells from hepatectomized animals [26].
• CONCLUSIONS: M6P/IGF-II receptor upregulation may be a key factor in the in vivo control of TGF-beta1 activity and responsible for the tissue specificity of TGF-beta1 action after irradiation [27].

Other interactions of Igf2

• IGF-I and IGF-II but not insulin evoked a marked decrease of IGFBP-4 as early as 4 hours after treatment [28].
• Thus, a marked dissociation can be observed between the rapid insulin-like action of MSA and its inhibitory effects on the affinity labeling of the type II receptor by 125I-IGF I [14].
• Under normal physiology, IGF-II expression is restricted to the mesenchymal support structures of the brain, including the choroid plexus, where its expression is coincident with that of IGFBP-2 [21].
• In the absence of IGFBP (fresh medium), glycogenesis, and DNA synthesis were stimulated by IGF-II and insulin [19].
• Our results suggest that in the case of DNA synthesis the effects of IGF-II are mediated via the IGF-I receptor and those of insulin via the insulin receptor, whereas in the case of glycogenesis both are mediated via the insulin receptor [19].

Analytical, diagnostic and therapeutic context of Igf2

• The present study was undertaken to evaluate the expression of Igf2 and Igf1r transcript by RT-PCR in the post-implantation embryos obtained after paternal tamoxifen treatment [4].
• A radioimmunoassay was utilized to measure MSA levels in sera from fetal, maternal, and young rats [20].
• IGF-II mRNA levels tended to decrease in regressing tumors following ovariectomy, and they markedly increased upon reactivation of tumor growth with hormone repletion [29].
• Concurrent studies of Sm/IGF stimulation of 3H-thymidine incorporation revealed that these cells were most sensitive to Sm-C/IGF I, followed by IGF II and MSA, and insulin [30].
• To demonstrate that IGF-II, IGFBP, and IGF receptor (-R) expression alters in response to a penetrating CNS injury, we used the techniques of ribonuclease protection assay, in situ hybridization, immunohistochemistry, Western blotting, and RIA [21].

References