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Gene Review

IGF2  -  insulin-like growth factor 2

Homo sapiens

Synonyms: C11orf43, FLJ44734, IGF-II, Insulin-like growth factor II, PP1446, ...
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Disease relevance of IGF2


Psychiatry related information on IGF2


High impact information on IGF2

  • This epigenetic defect is associated with, and probably responsible for, relaxation of imprinting and biallelic expression of H19 and downregulation of IGF2 [11].
  • Microdeletion and IGF2 loss of imprinting in a cascade causing Beckwith-Wiedemann syndrome with Wilms' tumor [12].
  • These results suggest that increased in utero expression of paternal INS or IGF2 due to the class I INS VNTR allele may predispose offspring to postnatal fat deposition [13].
  • We found that KVLQT1 spans much of the interval between p57KIP2 and IGF2, and that it is also imprinted [14].
  • We and others have identified three imprinted human genes on 11p15.5, IGF2, H19, and p57KIP2, although the latter gene is separated by 700 kb from the other two, and it is unclear whether there are other imprinted genes within this large interval [14].

Chemical compound and disease context of IGF2


Biological context of IGF2

  • Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility [20].
  • HLA-DR4-positive diabetics showed an increased risk associated with common variants at polymorphic sites in a 19-kilobase segment spanned by the 5' INS VNTR and the third intron of the gene for insulin-like growth factor II (IGF2) [20].
  • These marked changes resulted in demethylation of repeated sequences, loss of insulin-like growth factor II (IGF2) imprinting, abrogation of silencing of the tumour suppressor gene p16INK4a, and growth suppression [21].
  • Inhibition of the synthesis of putative trans imprinting factors with cycloheximide led to loss of IGF2 imprinting in normal cultured fibroblasts, suggesting that normal cells produce proteins that act in trans to induce or maintain genomic imprinting [22].
  • In tetraploid hybrid cells, however, normal IGF2 imprinting was permanently restored in the tumor genome [22].

Anatomical context of IGF2

  • But in one child who had generalized somatic overgrowth, IGF2 was transcribed from both alleles in her kidney, peripheral blood leukocytes and Wilms' tumour [2].
  • In this study we have exploited the high affinity and specificity of IGF-binding protein 4 (IGF-BP4) and IGF-BP5 for IGF1 and IGF2 to determine whether these growth factors are involved in the nerve sprouting reaction in paralyzed skeletal muscle [23].
  • The human Achaete-Scute homologue 2 (ASCL2,HASH2) maps to chromosome 11p15.5, close to IGF2 and is expressed in extravillus trophoblasts [24].
  • The forced down-regulation of CTCF expression using small interfering RNA in imprinted prostate cell lines resulted in an increase in IGF2 expression and a relaxation of imprinting [25].
  • In thymus, class III alleles were associated with an IGF2 mRNA level of 4.7 +/- 0.9 (mean +/- SE, arbitrary units, n = 12) compared with 4.7 +/- 1.3 for class I alleles (n = 17) [26].

Associations of IGF2 with chemical compounds

  • Deregulation of one or more imprinted genes located at chromosome 11p15.5, of which insulin-like growth factor 2 (IGF2) is the most likely candidate, is believed to cause BWS, whereas the etiology of KTWS is completely obscure [27].
  • Bisulfite sequencing reveals IGF2 LOI occurs with biallelic CpG methylation of the CTCF-binding site, while H19 LOI occurs with biallelic hypomethylation of this site [28].
  • Using a bromodeoxyuridine incorporation method to detect replicated DNA, we studied allele-specific replication of several sites within the human Prader-Willi/Angelman and IGF2/H19 imprinted regions [29].
  • We also analyzed the methylation status of these sites in human-mouse somatic-cell-hybrid clones containing a single copy of human chromosome 11 and which were treated with 5-aza-2'-deoxycytidine (5-aza-CdR) to yield clones which expressed human IGF2 and H19 mutually exclusively of each other [30].
  • RESULTS: In response to caloric surplus, fasting plasma insulin (p < 0.05) and OGTT insulin (p = 0.004) but not glucose area, increased more among the subjects with IGF2 Apa I GG (n = 12) than those with AA + AG (n = 12) [31].

Physical interactions of IGF2

  • In contrast, iodinated IGF-2 bound to a receptor where IGF-1 and IGF-2 were equipotent [32].
  • In most of the clones, a correlation between methylation of the sixth CTCF-binding site and expression of IGF2 was observed [30].
  • The remaining allele in 6/11 (55%) LOH patients contained mutations in either the mannose 6-phosphate or the IGF2 binding domain of the M6P/IGF2R [33].
  • Previous studies demonstrated that IGF-II binds directly to vitronectin (VN), whereas IGF-I binds poorly [34].
  • In control subjects, 89.8 +/- 4.47% of serum total IGF-I and 77.3 +/- 9.4% of serum total IGF-II were bound to serum IGFBP-3 [35].

Enzymatic interactions of IGF2


Regulatory relationships of IGF2

  • Our data suggest a novel mechanism for IGF2 imprinting regulation, that is, the reduction of CTCF expression in the control of IGF2 imprinting [25].
  • Both IGF-I and IGF-II were capable of inducing a decrease in IGFBP-4; however, IGF-II was more effective [37].
  • In human fibroblasts, IGF-1 stimulated DNA synthesis up to 300% for IGF-1 and up to 200% for IGF-2 [38].
  • IGFBP-2 production was also inhibited by IGF-II and [Leu27]IGF-II (ED50 for both 3 ng/mL) but not by IGF-I at up to 30 ng/mL [39].
  • A soluble, circulating form of IGF2R inhibits IGF-II mediated DNA synthesis and may therefore restrain fetal growth [18].
  • PIK3R3 knockdown inhibited IGF2-induced growth of GBM-derived neurospheres [40].

Other interactions of IGF2

  • This study indicates (a) that IGF-II is potentially capable of autocrine regulation on the basolateral side of HT29-D4-GAL cell, and (b) that IGFBP-6 has a unique pattern of secretory polarity [41].
  • Messenger RNAs for IGF-1, IGF-2, and IGFBP-4 were detected by Northern analysis [42].
  • Surprisingly, LOI of LIT1 was not linked to LOI of insulin-like growth factor II (IGF2), which was found in 2 of 10 (20%) BWS patients, even though LOI of IGF2 occurs frequently in Wilms and other tumors, and in some patients with BWS [43].
  • We have confirmed the existence of insulators in H19 DMR and discovered two novel insulators in the IGF2 gene [44].
  • We examined allelic methylation ratios at DMRs within the IGF2/H19- and IGF2R-loci in a panel of 48 three-generation families [45].

Analytical, diagnostic and therapeutic context of IGF2


  1. Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome. Sparago, A., Cerrato, F., Vernucci, M., Ferrero, G.B., Silengo, M.C., Riccio, A. Nat. Genet. (2004) [Pubmed]
  2. Constitutional relaxation of insulin-like growth factor II gene imprinting associated with Wilms' tumour and gigantism. Ogawa, O., Becroft, D.M., Morison, I.M., Eccles, M.R., Skeen, J.E., Mauger, D.C., Reeve, A.E. Nat. Genet. (1993) [Pubmed]
  3. Gain of imprinting at chromosome 11p15: A pathogenetic mechanism identified in human hepatocarcinomas. Schwienbacher, C., Gramantieri, L., Scelfo, R., Veronese, A., Calin, G.A., Bolondi, L., Croce, C.M., Barbanti-Brodano, G., Negrini, M. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  4. Haplotypic analyses of the IGF2-INS-TH gene cluster in relation to cardiovascular risk traits. Rodríguez, S., Gaunt, T.R., O'Dell, S.D., Chen, X.H., Gu, D., Hawe, E., Miller, G.J., Humphries, S.E., Day, I.N. Hum. Mol. Genet. (2004) [Pubmed]
  5. Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2. Cui, H., Onyango, P., Brandenburg, S., Wu, Y., Hsieh, C.L., Feinberg, A.P. Cancer Res. (2002) [Pubmed]
  6. Association between the insulin-like growth factor 2 gene (IGF2) and scores on the Eating Attitudes Test in nonclinical subjects: a family-based study. Bachner-Melman, R., Zohar, A.H., Nemanov, L., Heresco-Levy, U., Gritsenko, I., Ebstein, R.P. The American journal of psychiatry. (2005) [Pubmed]
  7. Expression of mRNA for the insulin-like growth factors and their receptors in human preimplantation embryos. Lighten, A.D., Hardy, K., Winston, R.M., Moore, G.E. Mol. Reprod. Dev. (1997) [Pubmed]
  8. Refined Association Mapping for a Quantitative Trait: Weight in the H19-IGF2-INS-TH Region. Zhang, W., Maniatis, N., Rodriguez, S., Miller, G.J., Day, I.N., Gaunt, T.R., Collins, A., Morton, N.E. Ann. Hum. Genet. (2006) [Pubmed]
  9. Insulin-like growth factors and insulin-like growth factor binding proteins in cerebrospinal fluid and serum of patients with dementia of the Alzheimer type. Tham, A., Nordberg, A., Grissom, F.E., Carlsson-Skwirut, C., Viitanen, M., Sara, V.R. Journal of neural transmission. Parkinson's disease and dementia section. (1993) [Pubmed]
  10. Insulin-like growth factor binding protein-1 inhibits the mitogenic effect of insulin-like growth factors and progestins in human endometrial stromal cells. Frost, R.A., Mazella, J., Tseng, L. Biol. Reprod. (1993) [Pubmed]
  11. Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome. Gicquel, C., Rossignol, S., Cabrol, S., Houang, M., Steunou, V., Barbu, V., Danton, F., Thibaud, N., Le Merrer, M., Burglen, L., Bertrand, A.M., Netchine, I., Le Bouc, Y. Nat. Genet. (2005) [Pubmed]
  12. Microdeletion and IGF2 loss of imprinting in a cascade causing Beckwith-Wiedemann syndrome with Wilms' tumor. Prawitt, D., Enklaar, T., Gärtner-Rupprecht, B., Spangenberg, C., Lausch, E., Reutzel, D., Fees, S., Korzon, M., Brozek, I., Limon, J., Housman, D.E., Pelletier, J., Zabel, B. Nat. Genet. (2005) [Pubmed]
  13. Paternal transmission of the very common class I INS VNTR alleles predisposes to childhood obesity. Le Stunff, C., Fallin, D., Bougnères, P. Nat. Genet. (2001) [Pubmed]
  14. Human KVLQT1 gene shows tissue-specific imprinting and encompasses Beckwith-Wiedemann syndrome chromosomal rearrangements. Lee, M.P., Hu, R.J., Johnson, L.A., Feinberg, A.P. Nat. Genet. (1997) [Pubmed]
  15. Imprinting and expression of insulin-like growth factor-II and H19 in normal breast tissue and breast tumor. Yballe, C.M., Vu, T.H., Hoffman, A.R. J. Clin. Endocrinol. Metab. (1996) [Pubmed]
  16. Insulin-like growth factor 2 and insulin-like growth factor binding protein 2 expression in hepatoblastoma. Akmal, S.N., Yun, K., MacLay, J., Higami, Y., Ikeda, T. Hum. Pathol. (1995) [Pubmed]
  17. IGF2 is critical for tumorigenesis by synovial sarcoma oncoprotein SYT-SSX1. Sun, Y., Gao, D., Liu, Y., Huang, J., Lessnick, S., Tanaka, S. Oncogene (2006) [Pubmed]
  18. Size at birth and cord blood levels of insulin, insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-3, and the soluble IGF-II/mannose-6-phosphate receptor in term human infants. The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. Ong, K., Kratzsch, J., Kiess, W., Costello, M., Scott, C., Dunger, D. J. Clin. Endocrinol. Metab. (2000) [Pubmed]
  19. Regulation of the insulin-like growth factors and their binding proteins by glucocorticoid and growth hormone in nonislet cell tumor hypoglycemia. Baxter, R.C., Holman, S.R., Corbould, A., Stranks, S., Ho, P.J., Braund, W. J. Clin. Endocrinol. Metab. (1995) [Pubmed]
  20. Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility. Julier, C., Hyer, R.N., Davies, J., Merlin, F., Soularue, P., Briant, L., Cathelineau, G., Deschamps, I., Rotter, J.I., Froguel, P. Nature (1991) [Pubmed]
  21. DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Rhee, I., Bachman, K.E., Park, B.H., Jair, K.W., Yen, R.W., Schuebel, K.E., Cui, H., Feinberg, A.P., Lengauer, C., Kinzler, K.W., Baylin, S.B., Vogelstein, B. Nature (2002) [Pubmed]
  22. Correction of aberrant imprinting of IGF2 in human tumors by nuclear transfer-induced epigenetic reprogramming. Chen, H.L., Li, T., Qiu, X.W., Wu, J., Ling, J.Q., Sun, Z.H., Wang, W., Chen, W., Hou, A., Vu, T.H., Hoffman, A.R., Hu, J.F. EMBO J. (2006) [Pubmed]
  23. Role of muscle insulin-like growth factors in nerve sprouting: suppression of terminal sprouting in paralyzed muscle by IGF-binding protein 4. Caroni, P., Schneider, C., Kiefer, M.C., Zapf, J. J. Cell Biol. (1994) [Pubmed]
  24. The human Achaete-Scute homologue 2 (ASCL2,HASH2) maps to chromosome 11p15.5, close to IGF2 and is expressed in extravillus trophoblasts. Alders, M., Hodges, M., Hadjantonakis, A.K., Postmus, J., van Wijk, I., Bliek, J., de Meulemeester, M., Westerveld, A., Guillemot, F., Oudejans, C., Little, P., Mannens, M. Hum. Mol. Genet. (1997) [Pubmed]
  25. A loss of insulin-like growth factor-2 imprinting is modulated by CCCTC-binding factor down-regulation at senescence in human epithelial cells. Fu, V.X., Schwarze, S.R., Kenowski, M.L., Leblanc, S., Svaren, J., Jarrard, D.F. J. Biol. Chem. (2004) [Pubmed]
  26. A functional analysis of the role of IGF2 in IDDM2-encoded susceptibility to type 1 diabetes. Vafiadis, P., Grabs, R., Goodyer, C.G., Colle, E., Polychronakos, C. Diabetes (1998) [Pubmed]
  27. Relaxation of insulin-like growth factor 2 imprinting and discordant methylation at KvDMR1 in two first cousins affected by Beckwith-Wiedemann and Klippel-Trenaunay-Weber syndromes. Sperandeo, M.P., Ungaro, P., Vernucci, M., Pedone, P.V., Cerrato, F., Perone, L., Casola, S., Cubellis, M.V., Bruni, C.B., Andria, G., Sebastio, G., Riccio, A. Am. J. Hum. Genet. (2000) [Pubmed]
  28. Loss of imprinting of IGF2 and H19 in osteosarcoma is accompanied by reciprocal methylation changes of a CTCF-binding site. Ulaner, G.A., Vu, T.H., Li, T., Hu, J.F., Yao, X.M., Yang, Y., Gorlick, R., Meyers, P., Healey, J., Ladanyi, M., Hoffman, A.R. Hum. Mol. Genet. (2003) [Pubmed]
  29. Allele-specific replication timing in imprinted domains: absence of asynchrony at several loci. Kawame, H., Gartler, S.M., Hansen, R.S. Hum. Mol. Genet. (1995) [Pubmed]
  30. Large scale mapping of methylcytosines in CTCF-binding sites in the human H19 promoter and aberrant hypomethylation in human bladder cancer. Takai, D., Gonzales, F.A., Tsai, Y.C., Thayer, M.J., Jones, P.A. Hum. Mol. Genet. (2001) [Pubmed]
  31. Insulin-like growth factor 2 (IGF2 ) and IGF-binding protein 1 (IGFBP1) gene variants are associated with overfeeding-induced metabolic changes. Ukkola, O., Sun, G., Bouchard, C. Diabetologia (2001) [Pubmed]
  32. Ontogenesis of somatomedin and insulin receptors in the human fetus. Sara, V.R., Hall, K., Misaki, M., Fryklund, L., Christensen, N., Wetterberg, L. J. Clin. Invest. (1983) [Pubmed]
  33. M6P/IGF2R is mutated in squamous cell carcinoma of the lung. Kong, F.M., Anscher, M.S., Washington, M.K., Killian, J.K., Jirtle, R.L. Oncogene (2000) [Pubmed]
  34. Structural and functional evidence for the interaction of insulin-like growth factors (IGFs) and IGF binding proteins with vitronectin. Kricker, J.A., Towne, C.L., Firth, S.M., Herington, A.C., Upton, Z. Endocrinology (2003) [Pubmed]
  35. Insulin-like growth factor binding protein (IGFBP)-3-bound IGF-I and IGFBP-3-bound IGF-II in growth hormone deficiency. Belgorosky, A., Rivarola, M.A. Horm. Res. (1999) [Pubmed]
  36. PTEN modulates insulin-like growth factor II (IGF-II)-mediated signaling; the protein phosphatase activity of PTEN downregulates IGF-II expression in hepatoma cells. Kang-Park, S., Lee, Y.I., Lee, Y.I. FEBS Lett. (2003) [Pubmed]
  37. Regulation of insulin-like growth factor binding protein 4 by a specific insulin-like growth factor binding protein 4 proteinase in normal human osteoblast-like cells: implications in bone cell physiology. Durham, S.K., Kiefer, M.C., Riggs, B.L., Conover, C.A. J. Bone Miner. Res. (1994) [Pubmed]
  38. Effect of recombinant IGF binding protein-1 on primary cultures of human keratinocytes and fibroblasts: selective enhancement of IGF-1 but not IGF-2-induced cell proliferation. Kratz, G., Lake, M., Ljungström, K., Forsberg, G., Haegerstrand, A., Gidlund, M. Exp. Cell Res. (1992) [Pubmed]
  39. Regulation of insulin-like growth factor binding protein production by human luteinizing granulosa cells cultured in defined medium. Cataldo, N.A., Woodruff, T.K., Giudice, L.C. J. Clin. Endocrinol. Metab. (1993) [Pubmed]
  40. Identification of IGF2 signaling through phosphoinositide-3-kinase regulatory subunit 3 as a growth-promoting axis in glioblastoma. Soroceanu, L., Kharbanda, S., Chen, R., Soriano, R.H., Aldape, K., Misra, A., Zha, J., Forrest, W.F., Nigro, J.M., Modrusan, Z., Feuerstein, B.G., Phillips, H.S. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  41. Cell polarity of the insulin-like growth factor system in human intestinal epithelial cells. Unique apical sorting of insulin-like growth factor binding protein-6 in differentiated human colon cancer cells. Remacle-Bonnet, M., Garrouste, F., el Atiq, F., Marvaldi, J., Pommier, G. J. Clin. Invest. (1995) [Pubmed]
  42. Insulinlike growth factor-binding protein modulates the growth response to insulinlike growth factor 1 by human gastric cancer cells. Guo, Y.S., Beauchamp, R.D., Jin, G.F., Townsend, C.M., Thompson, J.C. Gastroenterology (1993) [Pubmed]
  43. Loss of imprinting of a paternally expressed transcript, with antisense orientation to KVLQT1, occurs frequently in Beckwith-Wiedemann syndrome and is independent of insulin-like growth factor II imprinting. Lee, M.P., DeBaun, M.R., Mitsuya, K., Galonek, H.L., Brandenburg, S., Oshimura, M., Feinberg, A.P. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  44. Insulator and silencer sequences in the imprinted region of human chromosome 11p15.5. Du, M., Beatty, L.G., Zhou, W., Lew, J., Schoenherr, C., Weksberg, R., Sadowski, P.D. Hum. Mol. Genet. (2003) [Pubmed]
  45. Familial aggregation of abnormal methylation of parental alleles at the IGF2/H19 and IGF2R differentially methylated regions. Sandovici, I., Leppert, M., Hawk, P.R., Suarez, A., Linares, Y., Sapienza, C. Hum. Mol. Genet. (2003) [Pubmed]
  46. Molecular characterization of cytogenetic alterations associated with the Beckwith-Wiedemann syndrome (BWS) phenotype refines the localization and suggests the gene for BWS is imprinted. Weksberg, R., Teshima, I., Williams, B.R., Greenberg, C.R., Pueschel, S.M., Chernos, J.E., Fowlow, S.B., Hoyme, E., Anderson, I.J., Whiteman, D.A. Hum. Mol. Genet. (1993) [Pubmed]
  47. Polymerase chain reaction (PCR) for detection of ApaI polymorphism at the insulin like growth factor II gene (IGF2). Tadokoro, K., Fujii, H., Inoue, T., Yamada, M. Nucleic Acids Res. (1991) [Pubmed]
  48. Pediatric adrenocortical tumors: molecular events leading to insulin-like growth factor II gene overexpression. Wilkin, F., Gagné, N., Paquette, J., Oligny, L.L., Deal, C. J. Clin. Endocrinol. Metab. (2000) [Pubmed]
  49. Impact of constitutive IGF1/IGF2 stimulation on the transcriptional program of human breast cancer cells. Pacher, M., Seewald, M.J., Mikula, M., Oehler, S., Mogg, M., Vinatzer, U., Eger, A., Schweifer, N., Varecka, R., Sommergruber, W., Mikulits, W., Schreiber, M. Carcinogenesis (2007) [Pubmed]
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