Disease relevance of IGF2

• Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome [1].
• We have examined the imprinting of the insulin-like growth factor II gene (IGF2) in ten normal kidney samples from children with renal embryonal neoplasms [2].
• As compared with matched normal liver tissue, hepatocellular carcinomas showed extinction or significant reduction of expression of one of the alleles of the CDKN1C, SLC22A1L, and IGF2 genes [3].
• The IGF2-INS-TH genomic region has been implicated in various common disorders including the metabolic syndrome, type 2 diabetes and coronary heart disease (CHD) [4].
• Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2 [5].

Psychiatry related information on IGF2

• OBJECTIVE: An interesting candidate gene for eating disorders is the gene for insulin-like growth factor 2 (IGF2) [6].
• To study the role of the insulin-like growth factors in early human development, the timing of gene expression of insulin, IGF1, IGF2, and their receptors was analysed [7].
• All the evidence for association came from IGF2, with P= 0.007 for height-adjusted weight and P= 0.019 for weight additionally adjusted for smoking and alcohol drinking [8].
• After acid gel-chromatography cerebrospinal fluid and serum levels of immunoreactive insulin-like growth factor 1 and 2 (IGF-1 and IGF-2) were determined in patients with dementia of the Alzheimer type (AD) and in healthy subjects [9].
• In a time study, IGF-I or IGF-II stimulated DNA synthesis 3-fold in 24 h [10].

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

• We examined 18 fresh-frozen (FF) breast tumors with their adjacent normal breast tissue and 14 sets of paraffin-embedded formalin-fixed tissues for IGF2 and H19 gene expression and imprinting [15].
• The expression of insulin-like growth factor 2 (IGF2) and insulin-like growth factor binding protein 2 (IGFBP2) in 11 cases of hepatoblastoma was studied by means of in situ mRNA hybridization using digoxigenin (DIG)-labeled riboprobes [16].
• We also found a loss of imprinting (LOI) for Igf2 in a limited number of primary synovial sarcomas despite demethylation of CpG dinucleotides critical for maintaining imprinting [17].
• IGF-II was weakly related to ponderal index (r = 0.18; P < 0.05) and placental weight (r = 0.18; P < 0.05), and the molar ratio of IGF-II to IGF2R was also related to birth weight (r = 0.15; P < 0.05) [18].
• Although prednisolone and GH reverse hypoglycemia by different mechanisms, with only prednisolone suppressing tumor IGF-II secretion, both increase the formation of ternary IGF-IGFBP-3 complexes [19].

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

• PTEN expression induced decreased Sp1 DNA binding by dephosphorylating Sp1 and interfered with transcriptional transactivation of IGF-II by HBx in hepatoma cells [36].

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

• Somatic cell hybrids, Southern blotting and fluorescent in situ hybridization (FISH) showed that both breakpoints were between D11S12 and the insulin-like growth factor 2 (IGF2) gene [46].
• Polymerase chain reaction (PCR) for detection of ApaI polymorphism at the insulin like growth factor II gene (IGF2) [47].
• Consistent with its profile of metabolic actions, an association has been reported between a single nucleotide polymorphism (SNP) in the 3' untranslated region of the IGF2 gene (ApaI) and body mass index [6].
• We investigated all 4 tumors for chromosome 11 structural abnormalities (11p15.5 to 11q23), IGF2 and H19 expression by competitive RT-PCR analysis, and IGF2 methylation patterns by Southern analysis [48].
• Conversely, IGF1 and IGF2 overexpression potently increased cellular proliferation rates and the efficiency of tumor formation in mouse xenograft experiments, whereas the resistance to chemotherapeutic drugs such as taxol was unaltered [49].

References