Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF2R) functions in the intracellular trafficking of lysosomal enzymes, the activation of the potent growth inhibitor, transforming growth factor beta 2, and the degradation of IGF2 (ref. 1), a mitogen often overproduced in tumours. We have recently shown that 70% of human hepatocellular tumours have loss of heterozygosity (LOH) at the M6P/IGF2R locus which maps to chromosome 6q26-q27 (ref. 8). Using a coarse screen, we have now identified point mutations in the remaining allele of 25% of human hepatocellular carcinomas (HCCs) with LOH. These mutations give rise to truncated receptor protein and significant amino acid substitutions, and provide evidence that the M6P/IGF2R gene functions as a tumour suppressor in human liver carcinogenesis.
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PMID:M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity. 749 29

The insulin-like growth factor-II (IGF2) and H19 genes are imprinted in mouse and human, with expression of the paternal IGF2 and maternal H19 alleles. IGF2 undergoes loss of imprinting (LOI) in most Wilms' tumours (WT). We now show that: (i) LOI of IGF2 is associated with a 80-fold down regulation of H19 expression; (ii) these changes are associated with alterations in parental-origin-specific, tissue-independent sites of DNA methylation in the H19 promoter; and (iii) loss of heterozygosity is also associated with loss of H19 expression. Thus, imprinting of a large domain of the maternal chromosome results in a reversal to a paternal epigenotype. These data also suggest an epigenetic mechanism for inactivation of H19 as a tumour suppressor gene.
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PMID:Loss of imprinting of IGF2 is linked to reduced expression and abnormal methylation of H19 in Wilms' tumour. 792 Jun 65

To test the potential role of H19 as a tumour suppressor gene we have examined its expression and DNA methylation in Wilms' tumours (WTs). In most WTs (18/25), H19 RNA was reduced at least 20-fold from fetal kidney levels. Of the expression-negative tumours ten retained 11p15.5 heterozygosity: in nine of these, H19 DNA was biallelically hypermethylated and in two cases hypermethylation locally restricted to H19 sequences was also present in the non-neoplastic kidney parenchyma. IGF2 mRNA was expressed in most but not all WTs and expression patterns were consistent with IGF2/H19 enhancer competition without obligate inverse coupling. These observations implicate genetic and epigenetic inactivation of H19 in Wilms' tumorigenesis.
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PMID:Epigenetic lesions at the H19 locus in Wilms' tumour patients. 792 Jun 66

Although the occurrence of bladder cancer is common, the molecular events underlying the pathogenesis of this cancer remain ill-defined. A loss of heterozygosity (LOH) at specific chromosomal loci may predispose individuals to the development of bladder cancer but this has not been examined in detail. Furthermore, the role that deletion or inactivation of putative tumour suppressor genes might play in the genesis of bladder cancer has not been established. In this study, allelic deletion analysis on the short arm of chromosome 17 of patients with primary bladder tumours failed to show deletion at 17p13 (0/7), a region known to contain the p53 tumour suppressor gene. Chromosome 11p15 showed allelic deletion at the IGF2 locus (2/7: 29%) and the PTH locus (1/11: 9%). However, no deletion was observed at the CALCA locus (0/6). LOH at 11p13, a region containing the Wilm's tumour suppressor gene (WT1), was also studied. Analysis of LOH at 11p13 showed deletion at the CAT locus (13/18: 72%), the delta J/D11S414 locus (5/15: 33%), the WT1 locus (7/14: 50%) and the FSHB locus (6/16: 38%). The significance of these findings is discussed.
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PMID:Loss of heterozygosity on chromosome 11p13 in primary bladder carcinoma. 810 Feb 10

Activation of the silent maternal IGF2 allele has recently been found in approximately half of Wilms' tumour (WTs) examined. This process of imprint relaxation leads to biallelic expression of IGF2 and it has been suggested that this is a key event in the onset of some WTs. Although it has previously been proposed that the 11p15 chromosome region contains a growth-promoting gene and a tumour suppressor gene, the simplest explanation is that increased expression of the IGF2 gene is responsible for somatic overgrowth in the BWS and predisposition to tumours. This model explains overgrowth in BWS cases with unbalanced translocations with paternal dup(11p), and cases with balanced maternal translocations which are physically close to the IGF2 gene. Maternal translocations are envisaged to disrupt the maternal IGF2 imprint by a mechanism similar to the position-effect variegation mechanism in Drosophila. Relaxation of IGF2 imprinting has also been detected in several patients with the BWS syndrome and a patient with gigantism and Wilms' tumour. Recent gene disruption experiments have shown that inactivation of the mouse h19 gene leads to biallelic lgf2 expression and extensive proportional overgrowth. This mouse model has parallels with the BWS and WT where it has been found that biallelic IGF2 expression is accompanied by an epigenetic modification of the H19 gene. From these data it is possible to speculate that an epigenetic modification of the H19 gene may be the primary event leading to the relaxation of IGF2 imprinting.
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PMID:Role of genomic imprinting in Wilms' tumour and overgrowth disorders. 882 76

Genomic imprinting is an epigenetic chromosomal modification in the gamete or zygote causing preferential expression of a specific parental allele in somatic cells of the offspring. 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. We previously mapped an embryonal tumour suppressor gene to this region, as well as five balanced germline chromosomal rearrangement breakpoints from patients with Beckwith-Wiedemann syndrome (BWS), a condition characterized by prenatal overgrowth and cancer. We isolated the upstream exons of the previously identified gene KVLQT1, which causes the familial cardiac defect long-QT (LQT) syndrome. We found that KVLQT1 spans much of the interval between p57KIP2 and IGF2, and that it is also imprinted. We demonstrated that the gene is disrupted by chromosomal rearrangements in BWS patients, as well as by a balanced chromosomal translocation in an embryonal rhabdoid tumour. Furthermore, the lack of parent-of-origin effect in LQT syndrome appears to be due to relative lack of imprinting in the affected tissue, cardiac muscle, representing a novel mechanism for variable penetrance of a human disease gene.
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PMID:Human KVLQT1 gene shows tissue-specific imprinting and encompasses Beckwith-Wiedemann syndrome chromosomal rearrangements. 902 Aug 29

Wilms' tumor (WT) is an embryonal renal malignancy, which overexpresses insulin-like growth factor II (IGF-II), a fetal mitogen. Relaxation of parental imprinting of IGF2, the gene encoding IGF-II, is found in Wilms' tumors, suggesting an important role for IGF2 dosage in tumorigenesis. The IGF2R gene encodes a nonmitogenic receptor which targets IGF-II to the lysosomes for degradation and, therefore, inhibits the mitogenic function of IGF-II. The human IGF2R is imprinted in a proportion of normal individuals. To test the hypothesis that IGF2R imprinting predisposes to Wilms' tumor through the effect of decreased IGF2R dosage on IGF-II inactivation, we examined IGF2R imprinting in Wilms' tumors. Two transcribed CA repeat polymorphisms were used to distinguish the two alleles in the RT-PCR product. We observed that in 7/16 of Wilms' tumor patients, the paternal IGF2R was markedly but not completely repressed in both tumor and normal kidney. In one additional case, IGF2R was likewise imprinted in the tumor but not in the normal kidney. A similar imprinting was observed in fetal tissues and placenta prior to 20 weeks fetal age but not in term placenta or postnatal blood cells, indicating abnormal persistence of a fetal pattern in the kidneys of Wilms' patients. Genetic analysis showed association of the imprinting with a cis-acting locus. The high frequency of aberrant persistence of IGF2R imprinting in the kidneys of Wilms' tumor patients, which may be an embryonic feature, suggests that it is a predisposing factor in tumorigenesis. This is in accordance with evidence that IGF2R is a tumour suppressor in other types of malignancies.
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PMID:Aberrant imprinting of the insulin-like growth factor II receptor gene in Wilms' tumor. 907 Jun 52

Mouse p57(Kip2) arrests cells in G1 by functioning as a strong inhibitor of several G1 cyclin/Cdk complexes (Lee et al., 1995; Matsuoka et al., 1995; Sherr and Roberts, 1995). Human p57(KIP2) has been suggested to be a tumour suppressor gene because of its location at 11p15.5 which frequently undergoes maternal allele LOH in several types of cancer (Matsuoka et al., 1995; Sherr and Roberts, 1995; Hatada and Mukai, 1995). This suggestion was supported by the discovery that mouse p57(Kip2) is imprinted with expression from only the maternally inherited allele (Hatada and Mukai, 1995). Interestingly, p57(KIP2) is several hundred kilobases from the imprinted H19 and IGF2 genes which are involved in growth regulation (Hoovers et al., 1995). Here we show that human p57(KIP2) is imprinted with expression from the maternal allele. However, unlike the mouse, the imprinting is incomplete with significant expression from the paternal allele depending on the tissue examined. We have also shown that the imprinting of p57(KIP2) occurs independently of the H19/IGF2 domain and thus there must be at least two imprinted domains in 11p15.5. Finally, by examining Wilms tumours we have shown that following maternal 11p LOH, p57(KIP2) was expressed from the paternal allele. Therefore, p57(KIP2) cannot function as an imprinted tumour suppressor gene, at least in Wilms tumour.
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PMID:Human p57(KIP2) defines a new imprinted domain on chromosome 11p but is not a tumour suppressor gene in Wilms tumour. 912 69

cDNA subtraction was employed to uncover differences in gene expression between myeloproliferative polycythaemia vera (PV) and normal haematopoietic precursors. Following cDNA subtraction using mRNAs isolated from PV and normal CD34+/CD33- bone-marrow cells, expression of the tumour suppressor H19 was found to be low or absent in the PV sample. Low levels of H19 expression in PV patients were confirmed by in situ hybridization. Using semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) to examine expression in the pluripotent haematopoietic cell line FDCP-mix and single bone-marrow precursors, unambiguous IGF2 and H19 expression was demonstrated in normal haematopoietic precursors. Examination of individual bone-marrow precursors revealed that all IGF2-expressing haematopoietic precursors also co-expressed H19, indicating that H19 and IGF2 may be co-ordinately regulated during haematopoiesis. Analysis of FDCP-mix undergoing differentiation and single pluripotent and committed bone-marrow precursors revealed that the pattern of H19 expression coincided with the commitment to a single lineage. Taken together, these observations demonstrate that H19 and IGF2 are specifically expressed during haematopoiesis and that low levels of H19 expression are associated with PV and may contribute to the pathology of the disease.
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PMID:Expression of the imprinted tumour-suppressor gene H19 is tightly regulated during normal haematopoiesis and is reduced in haematopoietic precursors of patients with the myeloproliferative disease polycythaemia vera. 1064 Sep 93

Chromosome 7p alterations have been implicated in the development of Wilms' tumour (WT) by previous studies of tumour cytogenetics, and by our analysis of a constitutional translocation (t(1;7)(q42;p15)) in a child with WT and radial aplasia. We therefore used polymorphic microsatellite markers on 7p for a loss of heterozygosity (LOH) study, and found LOH in seven out of 77 informative WTs (9%). The common region of LOH was 7p15-7p22, which contains the region disrupted by the t(1;7) breakpoint. Four WTs with 7p LOH had other genetic changes; a germline WT1 mutation with 11p LOH, LOH at 11p, LOH at 16q, and loss of imprinting of IGF2. Analysis of three tumour-associated lesions from 7p LOH cases revealed a cystic nephroma-like area also having 7p LOH. However, a nephrogenic rest and a contralateral WT from the two other cases showed no 7p LOH. No particular clinical phenotype was associated with the WTs which showed 7p LOH. The frequency and pattern of 7p LOH demonstrated in our studies indicate the presence of a tumour suppressor gene at 7p involved in the development of Wilms' tumour.
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PMID:Loss of heterozygosity at 7p in Wilms' tumour development. 1064 84


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