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Gene Review

Igf2  -  insulin-like growth factor 2

Mus musculus

Synonyms: AL033362, IGF-II, Igf-2, Igf-II, Insulin-like growth factor II, ...
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Disease relevance of Igf2


Psychiatry related information on Igf2


High impact information on Igf2

  • Various chromatin models have been proposed that separate Igf2 and H19 into active and silent domains [7].
  • Here we used a GAL4 knock-in approach as well as the chromosome conformation capture technique to show that the differentially methylated regions in the imprinted genes Igf2 and H19 interact in mice [7].
  • CTCF maintains differential methylation at the Igf2/H19 locus [8].
  • The unmethylated maternal ICR is a chromatin boundary that prevents distant enhancers from activating Igf2 (refs. 3-6) [8].
  • Pancreatic islets produce Igf1 and Igf2, which bind to specific receptors on beta-cells [9].

Chemical compound and disease context of Igf2

  • The effect of IGF-II was evoked at nonstimulatory concentrations of glucose, was mediated by a pertussis toxin sensitive GTP-binding protein, was dependent on protein kinase C-induced phosphorylation, and was independent of changes in cytoplasmic free Ca2+ concentration [10].
  • Expression of IGF-II mRNA, however, was reduced in primary prostate cancer, metastatic lesions, and androgen-independent disease [11].
  • Plasma corticosterone levels in these mice are twofold higher than in controls, in contrast to similar plasma ACTH levels, thus indicating a direct effect of IGF-II on adrenal cell hyperplasia and function [12].
  • Stably transfected C2 muscle cell lines were established in which a mouse IGF-II cDNA was expressed in the antisense orientation relative to the constitutively active Moloney sarcoma virus promoter [13].
  • By using phospholipid vesicles reconstituted with human wild type or mutant M6P/IGF II receptors and pertussis toxin-sensitive G-proteins, no stimulation of GTP gamma S binding to or GTPase activity of G(i)2, G(o)1, or G(i)/G(o) mixtures were observed in response to 1 microM IGF II [14].

Biological context of Igf2


Anatomical context of Igf2

  • Here we show that deletion from the Igf2 gene of a transcript (P0) specifically expressed in the labyrinthine trophoblast of the placenta leads to reduced growth of the placenta, followed several days later by fetal growth restriction [16].
  • The closely linked H19 and Igf2 genes were activated after the blastocyst stage and often exhibited biallelic and monoallelic expression respectively in tissues of pregastrulation postimplantation-stage embryos, rather than reciprocal monoallelic modes as observed at later stages [17].
  • Full restoration of monoallelic methylation and expression was imposed on H19, Igf2, and Igf2r upon germ-line transmission [18].
  • These results establish that H19 and Igf2 utilize the same endoderm enhancers, but on different parental chromosomes [19].
  • In addition, the deletion results in a minor relaxation of Igf2 imprinting in skeletal muscle and tongue [5].

Associations of Igf2 with chemical compounds


Physical interactions of Igf2

  • Decreasing fetal demand genetically by removal of fetal Igf2 abolished up-regulation of both transport systems and reduced placental System A amino acid transport activity and expression of Slc38a2 in late gestation [21].
  • In most cells and tissues, IR binds IGF-II with relatively low affinity [26].
  • Notable among this group were the growth factor gene Igf2 and its binding protein Igfbp5 [27].
  • As R6 IGF-II binds with higher affinity to the type 2 receptor than canonical IGF-II or IGF-I, and insulin fails to interact, this suggests that the elevation of cyclic AMP in response to the other insulin related peptides (IRPs) is not through the type 2 receptor [28].
  • Here we document that point mutations of the nucleotides in physical contact with CTCF within the endogenous H19 ICR lead to loss of CTCF binding and Igf2 imprinting only when passaged through the female germline [29].

Enzymatic interactions of Igf2

  • The interactions between the enhancers and the genes are regulated by the DMR, which works as a selector by exerting dual functions: a methylated DMR on the paternal chromosome inactivates adjacent H19 and an unmethylated DMR on the maternal chromosome insulates Igf2 from the enhancers [30].

Regulatory relationships of Igf2

  • Loss of the maternal H19 gene induces changes in Igf2 methylation in both cis and trans [22].
  • In somatic cells, the maternally and paternally derived ICRs are hypo- and hypermethylated, respectively, with the former binding the insulator protein CCCTC-binding factor (CTCF) and acting to block access of enhancers to the Igf2 promoter [31].
  • IGF-II is up-regulated and myofibres are hypertrophied in regenerating soleus of mice lacking FGF6 [32].
  • In vitro TGFalpha treatment of mouse PE reactivated paternally expressed Igf2 gene in the PE and PP [33].
  • PRL was most efficacious in stimulating IGF-II gene transcription from promoter 3 of the mouse IGF-II gene in vitro [34].

Other interactions of Igf2


Analytical, diagnostic and therapeutic context of Igf2


  1. Transactivation of Igf2 in a mouse model of Beckwith-Wiedemann syndrome. Sun, F.L., Dean, W.L., Kelsey, G., Allen, N.D., Reik, W. Nature (1997) [Pubmed]
  2. Soluble IGF2 receptor rescues Apc(Min/+) intestinal adenoma progression induced by Igf2 loss of imprinting. Harper, J., Burns, J.L., Foulstone, E.J., Pignatelli, M., Zaina, S., Hassan, A.B. Cancer Res. (2006) [Pubmed]
  3. Patched target Igf2 is indispensable for the formation of medulloblastoma and rhabdomyosarcoma. Hahn, H., Wojnowski, L., Specht, K., Kappler, R., Calzada-Wack, J., Potter, D., Zimmer, A., Müller, U., Samson, E., Quintanilla-Martinez, L., Zimmer, A. J. Biol. Chem. (2000) [Pubmed]
  4. Tissue-specific changes in H19 methylation and expression in mice with hyperhomocysteinemia. Devlin, A.M., Bottiglieri, T., Domann, F.E., Lentz, S.R. J. Biol. Chem. (2005) [Pubmed]
  5. Deletion of a nuclease-sensitive region between the Igf2 and H19 genes leads to Igf2 misregulation and increased adiposity. Jones, B.K., Levorse, J., Tilghman, S.M. Hum. Mol. Genet. (2001) [Pubmed]
  6. Induction and peak gene expression of insulin-like growth factor II follow that of myogenin during differentiation of BC3H-1 muscle cells. Brown, E.J., Hsiao, D., Rosenthal, S.M. Biochem. Biophys. Res. Commun. (1992) [Pubmed]
  7. Interaction between differentially methylated regions partitions the imprinted genes Igf2 and H19 into parent-specific chromatin loops. Murrell, A., Heeson, S., Reik, W. Nat. Genet. (2004) [Pubmed]
  8. CTCF maintains differential methylation at the Igf2/H19 locus. Schoenherr, C.J., Levorse, J.M., Tilghman, S.M. Nat. Genet. (2003) [Pubmed]
  9. beta-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass. Kulkarni, R.N., Holzenberger, M., Shih, D.Q., Ozcan, U., Stoffel, M., Magnuson, M.A., Kahn, C.R. Nat. Genet. (2002) [Pubmed]
  10. Insulin-like growth factor II signaling through the insulin-like growth factor II/mannose-6-phosphate receptor promotes exocytosis in insulin-secreting cells. Zhang, Q., Tally, M., Larsson, O., Kennedy, R.T., Huang, L., Hall, K., Berggren, P.O. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  11. The insulin-like growth factor axis and prostate cancer: lessons from the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Kaplan, P.J., Mohan, S., Cohen, P., Foster, B.A., Greenberg, N.M. Cancer Res. (1999) [Pubmed]
  12. The role of the insulin-like growth factor system in adrenocortical tumourigenesis. Weber, M.M., Fottner, C., Wolf, E. Eur. J. Clin. Invest. (2000) [Pubmed]
  13. Insulin-like growth factor-II is an autocrine survival factor for differentiating myoblasts. Stewart, C.E., Rotwein, P. J. Biol. Chem. (1996) [Pubmed]
  14. Mannose 6-phosphate/insulin-like growth factor II receptor fails to interact with G-proteins. Analysis of mutant cytoplasmic receptor domains. Körner, C., Nürnberg, B., Uhde, M., Braulke, T. J. Biol. Chem. (1995) [Pubmed]
  15. Deletion of a silencer element in Igf2 results in loss of imprinting independent of H19. Constância, M., Dean, W., Lopes, S., Moore, T., Kelsey, G., Reik, W. Nat. Genet. (2000) [Pubmed]
  16. Placental-specific IGF-II is a major modulator of placental and fetal growth. Constância, M., Hemberger, M., Hughes, J., Dean, W., Ferguson-Smith, A., Fundele, R., Stewart, F., Kelsey, G., Fowden, A., Sibley, C., Reik, W. Nature (2002) [Pubmed]
  17. Allele-specific expression and total expression levels of imprinted genes during early mouse development: implications for imprinting mechanisms. Szabó, P.E., Mann, J.R. Genes Dev. (1995) [Pubmed]
  18. Germ-line passage is required for establishment of methylation and expression patterns of imprinted but not of nonimprinted genes. Tucker, K.L., Beard, C., Dausmann, J., Jackson-Grusby, L., Laird, P.W., Lei, H., Li, E., Jaenisch, R. Genes Dev. (1996) [Pubmed]
  19. An enhancer deletion affects both H19 and Igf2 expression. Leighton, P.A., Saam, J.R., Ingram, R.S., Stewart, C.L., Tilghman, S.M. Genes Dev. (1995) [Pubmed]
  20. Deletion of the H19 transcription unit reveals the existence of a putative imprinting control element. Ripoche, M.A., Kress, C., Poirier, F., Dandolo, L. Genes Dev. (1997) [Pubmed]
  21. Adaptation of nutrient supply to fetal demand in the mouse involves interaction between the Igf2 gene and placental transporter systems. Constância, M., Angiolini, E., Sandovici, I., Smith, P., Smith, R., Kelsey, G., Dean, W., Ferguson-Smith, A., Sibley, C.P., Reik, W., Fowden, A. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  22. Loss of the maternal H19 gene induces changes in Igf2 methylation in both cis and trans. Forné, T., Oswald, J., Dean, W., Saam, J.R., Bailleul, B., Dandolo, L., Tilghman, S.M., Walter, J., Reik, W. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  23. Calvariae from fetal mice with a disrupted Igf1 gene have reduced rates of collagen synthesis but maintain responsiveness to glucocorticoids. Woitge, H.W., Kream, B.E. J. Bone Miner. Res. (2000) [Pubmed]
  24. Modulation of Igf2 genomic imprinting in mice induced by 5-azacytidine, an inhibitor of DNA methylation. Hu, J.F., Nguyen, P.H., Pham, N.V., Vu, T.H., Hoffman, A.R. Mol. Endocrinol. (1997) [Pubmed]
  25. Igf2 deficiency results in delayed lung development at the end of gestation. Silva, D., Venihaki, M., Guo, W.H., Lopez, M.F. Endocrinology (2006) [Pubmed]
  26. Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Frasca, F., Pandini, G., Scalia, P., Sciacca, L., Mineo, R., Costantino, A., Goldfine, I.D., Belfiore, A., Vigneri, R. Mol. Cell. Biol. (1999) [Pubmed]
  27. cDNA microarrays detect activation of a myogenic transcription program by the PAX3-FKHR fusion oncogene. Khan, J., Bittner, M.L., Saal, L.H., Teichmann, U., Azorsa, D.O., Gooden, G.C., Pavan, W.J., Trent, J.M., Meltzer, P.S. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  28. Elevation of cyclic AMP levels in mouse embryonic stem cells by insulin related peptides. Parkin, M.D., McNulty, S., Schofield, P.N. Early pregnancy : biology and medicine : the official journal of the Society for the Investigation of Early Pregnancy. (1996) [Pubmed]
  29. The nucleotides responsible for the direct physical contact between the chromatin insulator protein CTCF and the H19 imprinting control region manifest parent of origin-specific long-distance insulation and methylation-free domains. Pant, V., Mariano, P., Kanduri, C., Mattsson, A., Lobanenkov, V., Heuchel, R., Ohlsson, R. Genes Dev. (2003) [Pubmed]
  30. Mechanisms of Igf2/H19 imprinting: DNA methylation, chromatin and long-distance gene regulation. Sasaki, H., Ishihara, K., Kato, R. J. Biochem. (2000) [Pubmed]
  31. Parent-of-origin-specific binding of nuclear hormone receptor complexes in the H19-Igf2 imprinting control region. Szabó, P.E., Pfeifer, G.P., Mann, J.R. Mol. Cell. Biol. (2004) [Pubmed]
  32. IGF-II is up-regulated and myofibres are hypertrophied in regenerating soleus of mice lacking FGF6. Armand, A.S., Lécolle, S., Launay, T., Pariset, C., Fiore, F., Della Gaspera, B., Birnbaum, D., Chanoine, C., Charbonnier, F. Exp. Cell Res. (2004) [Pubmed]
  33. TGFalpha reactivates imprinted Igf2 in the parthenogenetic mice embryos and placenta. Rostam Zadehl, J., Penkov, L.I., Klimov, E.A., Platonov, E.S., Sulimova, G.E. Genetika (2005) [Pubmed]
  34. Local insulin-like growth factor-II mediates prolactin-induced mammary gland development. Hovey, R.C., Harris, J., Hadsell, D.L., Lee, A.V., Ormandy, C.J., Vonderhaar, B.K. Mol. Endocrinol. (2003) [Pubmed]
  35. The mouse H19 locus mediates a transition between imprinted and non-imprinted DNA replication patterns. Greally, J.M., Starr, D.J., Hwang, S., Song, L., Jaarola, M., Zemel, S. Hum. Mol. Genet. (1998) [Pubmed]
  36. Dnmt1 overexpression causes genomic hypermethylation, loss of imprinting, and embryonic lethality. Biniszkiewicz, D., Gribnau, J., Ramsahoye, B., Gaudet, F., Eggan, K., Humpherys, D., Mastrangelo, M.A., Jun, Z., Walter, J., Jaenisch, R. Mol. Cell. Biol. (2002) [Pubmed]
  37. Paternal imprints can be established on the maternal Igf2-H19 locus without altering replication timing of DNA. Cerrato, F., Dean, W., Davies, K., Kagotani, K., Mitsuya, K., Okumura, K., Riccio, A., Reik, W. Hum. Mol. Genet. (2003) [Pubmed]
  38. Genomic imprinting controls matrix attachment regions in the Igf2 gene. Weber, M., Hagège, H., Murrell, A., Brunel, C., Reik, W., Cathala, G., Forné, T. Mol. Cell. Biol. (2003) [Pubmed]
  39. Insulin-like growth factor II supply modifies growth of intestinal adenoma in Apc(Min/+) mice. Hassan, A.B., Howell, J.A. Cancer Res. (2000) [Pubmed]
  40. Diethylnitrosamine induces long-lasting re-expression of insulin-like growth factor II during early stages of liver carcinogenesis in mice. Lahm, H., Gittner, K., Krebs, O., Sprague, L., Deml, E., Oesterle, D., Hoeflich, A., Wanke, R., Wolf, E. Growth Horm. IGF Res. (2002) [Pubmed]
  41. Expression of H19 and Igf2 genes in uniparental mouse ES cells during in vitro and in vivo differentiation. McKarney, L.A., Overall, M.L., Dziadek, M. Differentiation (1996) [Pubmed]
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