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Gene Review

Igf2  -  insulin-like growth factor 2

Rattus norvegicus

Synonyms: IGF-II, IGFII, Igf-2, Insulin-like growth factor II, MSA, ...
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Disease relevance of Igf2


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


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


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


  1. Genetic isolation of a chromosome 1 region affecting blood pressure in the spontaneously hypertensive rat. St Lezin, E., Liu, W., Wang, J.M., Wang, N., Kren, V., Krenova, D., Musilova, A., Zdobinska, M., Zidek, V., Lau, D., Pravenec, M. Hypertension (1997) [Pubmed]
  2. 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. Tsujiuchi, T., Sasaki, Y., Oka, Y., Kuniyasu, H., Konishi, Y., Tsutsumi, M. Mol. Carcinog. (2004) [Pubmed]
  3. Alterations of the M6p/Igf2 receptor gene in lung adenocarcinomas induced by N-nitrosobis(2-hydroxypropyl)amine in rats. Tsujiuchi, T., Sasaki, Y., Tsutsumi, M., Konishi, Y. Mol. Carcinog. (2003) [Pubmed]
  4. Effect of paternal tamoxifen on the expression of insulin-like growth factor 2 and insulin-like growth factor type 1 receptor in the post-implantation rat embryos. Kedia, N., Gill-Sharma, M.K., Parte, P., Juneja, H.S., Balasinor, N. Mol. Reprod. Dev. (2004) [Pubmed]
  5. Thymic expression of insulin-related genes in an animal model of autoimmune type 1 diabetes. Kecha-Kamoun, O., Achour, I., Martens, H., Collette, J., Lefebvre, P.J., Greiner, D.L., Geenen, V. Diabetes Metab. Res. Rev. (2001) [Pubmed]
  6. Proliferation of Buffalo rat liver cells in serum-free medium does not depend upon multiplication-stimulating activity (MSA). Nissley, S.P., Short, P.A., Rechler, M.M., Podskalny, J.M., Coon, H.G. Cell (1977) [Pubmed]
  7. Isolation of a cDNA clone encoding rat insulin-like growth factor-II precursor. Whitfield, H.J., Bruni, C.B., Frunzio, R., Terrell, J.E., Nissley, S.P., Rechler, M.M. Nature (1984) [Pubmed]
  8. Purification of an insulin-like growth factor II receptor from rat chondrosarcoma cells. August, G.P., Nissley, S.P., Kasuga, M., Lee, L., Greenstein, L., Rechler, M.M. J. Biol. Chem. (1983) [Pubmed]
  9. Effect of thyroxine administration on the IGF/IGF binding protein system in neonatal and adult thyroidectomized rats. Ramos, S., Goya, L., Alvarez, C., Martín, M.A., Pascual-Leone, A.M. J. Endocrinol. (2001) [Pubmed]
  10. Insulin-like growth factors reverse or arrest diabetic neuropathy: effects on hyperalgesia and impaired nerve regeneration in rats. Zhuang, H.X., Snyder, C.K., Pu, S.F., Ishii, D.N. Exp. Neurol. (1996) [Pubmed]
  11. Hypertrophy of cultured adult rat ventricular cardiomyocytes induced by antibodies against the insulin-like growth factor (IGF)-I or the IGF-I receptor is IGF-II-dependent. Huang, C.Y., Hao, L.Y., Buetow, D.E. Mol. Cell. Biochem. (2002) [Pubmed]
  12. Genetic isolation of a chromosome 1 region affecting susceptibility to hypertension-induced renal damage in the spontaneously hypertensive rat. St Lezin, E., Griffin, K.A., Picken, M., Churchill, M.C., Churchill, P.C., Kurtz, T.W., Liu, W., Wang, N., Kren, V., Zidek, V., Pravenec, M., Bidani, A.K. Hypertension (1999) [Pubmed]
  13. Mutations in the IGF-II pathway that confer resistance to lytic reovirus infection. Sheng, J., Organ, E.L., Hao, C., Wells, K.S., Ruley, H.E., Rubin, D.H. BMC Cell Biol. (2004) [Pubmed]
  14. The type I insulin-like growth factor receptor mediates the rapid effects of multiplication-stimulating activity on membrane transport systems in rat soleus muscle. Yu, K.T., Czech, M.P. J. Biol. Chem. (1984) [Pubmed]
  15. Demonstration of receptors for insulin and insulin-like growth factors on Swarm rat chondrosarcoma chondrocytes. Evidence that insulin stimulates proteoglycan synthesis through the insulin receptor. Foley, T.P., Nissley, S.P., Stevens, R.L., King, G.L., Hascall, V.C., Humbel, R.E., Short, P.A., Rechler, M.M. J. Biol. Chem. (1982) [Pubmed]
  16. Receptors for insulin-like growth factors and growth effects of multiplication-stimulating activity (rat insulin-like growth factor II) in rat embryo fibroblasts. Adams, S.O., Nissley, S.P., Kasuga, M., Foley, T.P., Rechler, M.M. Endocrinology (1983) [Pubmed]
  17. Tissue, developmental, and metabolic regulation of messenger ribonucleic acid encoding a rat insulin-like growth factor-binding protein. Orlowski, C.C., Brown, A.L., Ooi, G.T., Yang, Y.W., Tseng, L.Y., Rechler, M.M. Endocrinology (1990) [Pubmed]
  18. Expression of the insulin-like growth factor (IGF)-I and -II and the IGF-I and -II receptor genes during postnatal development of the rat ovary. Levy, M.J., Hernandez, E.R., Adashi, E.Y., Stillman, R.J., Roberts, C.T., LeRoith, D. Endocrinology (1992) [Pubmed]
  19. Insulin-like growth factor (IGF) binding proteins modulate the glucocorticoid-dependent biological effects of IGF-II in cultured fetal rat hepatocytes. Menuelle, P., Babajko, S., Plas, C. Endocrinology (1999) [Pubmed]
  20. Increased levels of multiplication-stimulating activity, an insulin-like growth factor, in fetal rat serum. Moses, A.C., Nissley, S.P., Short, P.A., Rechler, M.M., White, R.M., Knight, A.B., Higa, O.Z. Proc. Natl. Acad. Sci. U.S.A. (1980) [Pubmed]
  21. Distinct sites of insulin-like growth factor (IGF)-II expression and localization in lesioned rat brain: possible roles of IGF binding proteins (IGFBPs) in the mediation of IGF-II activity. Walter, H.J., Berry, M., Hill, D.J., Cwyfan-Hughes, S., Holly, J.M., Logan, A. Endocrinology (1999) [Pubmed]
  22. Characterization of insulin-like growth factor binding proteins produced in the rat central nervous system. Ocrant, I., Fay, C.T., Parmelee, J.T. Endocrinology (1990) [Pubmed]
  23. Retinoic acid stimulates the transcription of insulin-like growth factor binding protein-6 in skeletal cells. Gabbitas, B., Canalis, E. J. Cell. Physiol. (1996) [Pubmed]
  24. Interactions of recombinant and platelet transforming growth factor-beta 1 precursor with the insulin-like growth factor II/mannose 6-phosphate receptor. Kovacina, K.S., Steele-Perkins, G., Purchio, A.F., Lioubin, M., Miyazono, K., Heldin, C.H., Roth, R.A. Biochem. Biophys. Res. Commun. (1989) [Pubmed]
  25. Transgenic mice overexpressing insulin-like growth factor-II in beta cells develop type 2 diabetes. Devedjian, J.C., George, M., Casellas, A., Pujol, A., Visa, J., Pelegrín, M., Gros, L., Bosch, F. J. Clin. Invest. (2000) [Pubmed]
  26. Insulin-like growth factor-II/mannose-6-phosphate receptors are increased in hepatocytes from regenerating rat liver. Scott, C.D., Baxter, R.C. Endocrinology (1990) [Pubmed]
  27. Upregulation and spatial shift in the localization of the mannose 6-phosphate/insulin-like growth factor II receptor during radiation enteropathy development in the rat. Wang, J., Richter, K.K., Sung, C.C., Hauer-Jensen, M. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. (1999) [Pubmed]
  28. Expression and insulin-like growth factor-dependent proteolysis of insulin-like growth factor-binding protein-4 are regulated by cell confluence in vascular smooth muscle cells. Kamyar, A., Pirola, C.J., Wang, H.M., Sharifi, B., Mohan, S., Forrester, J.S., Fagin, J.A. Circ. Res. (1994) [Pubmed]
  29. Hormonal regulation of insulin-like growth factor II and insulin-like growth factor binding protein expression by breast cancer cells in vivo: evidence for stromal epithelial interactions. Manni, A., Badger, B., Wei, L., Zaenglein, A., Grove, R., Khin, S., Heitjan, D., Shimasaki, S., Ling, N. Cancer Res. (1994) [Pubmed]
  30. Characterization of somatomedin/insulin-like growth factor receptors and correlation with biologic action in cultured neonatal rat astroglial cells. Han, V.K., Lauder, J.M., D'Ercole, A.J. J. Neurosci. (1987) [Pubmed]
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