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

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

The insulin-like growth factor II receptor mediates endocytosis of insulin-like growth factor II, resulting in growth factor degradation in lysosomes. This degradation is an important regulator of growth factor activity in vivo, as shown by the phenotype of receptor deficient mice. Recent evidence suggests that the insulin-like growth factor II receptor functions as a tumour suppressor in humans, and that loss of receptor function leads to increased levels of the growth factor in tumours. It is difficult to establish such a causal relationship in human tumours however, since most tumours have undergone several genetic changes by the time they are examined. Using mouse embryos deficient in receptor expression, and an insulin-like growth factor II-specific radioimmunoassay, we tested the hypothesis that lack of receptor function leads to local accumulation of insulin-like growth factor II. We found that mutant blood and skeletal muscle had excess insulin-like growth factor II, but that mutant lungs and liver had no accumulation. Mutant hearts had less growth factor than wild-type hearts, an unexpected observation, since the normal embryonic heart expresses very high levels of insulin-like growth factor II receptor, and mutant mice apparently die of congestive heart failure. The placentas of mutant mice were larger than those of wild-type, but this did not correlate with an excess of placental insulin-like growth factor II. These results indicate that lack of insulin-like growth factor II receptor can lead to local excess of the growth factor but that such excess is not a necessary consequence of receptor-deficiency.
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PMID:Variable accumulation of insulin-like growth factor II in mouse tissues deficient in insulin-like growth factor II receptor. 1064 96

Inactivation of tumour suppressor genes is central to the development of all common forms of human cancer. This inactivation often results from epigenetic silencing associated with hypermethylation rather than intragenic mutations. In human cells, the mechanisms underlying locus-specific or global methylation patterns remain unclear. The prototypic DNA methyltransferase, Dnmt1, accounts for most methylation in mouse cells, but human cancer cells lacking DNMT1 retain significant genomic methylation and associated gene silencing. We disrupted the human DNMT3b gene in a colorectal cancer cell line. This deletion reduced global DNA methylation by less than 3%. Surprisingly, however, genetic disruption of both DNMT1 and DNMT3b nearly eliminated methyltransferase activity, and reduced genomic DNA methylation by greater than 95%. 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. Here we demonstrate that two enzymes cooperatively maintain DNA methylation and gene silencing in human cancer cells, and provide compelling evidence that such methylation is essential for optimal neoplastic proliferation.
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PMID:DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. 1193 49

The study of the clonality of adrenocortical tumours (ACTs) has shown that adrenocortical cancers (ACCs) are of monoclonal origin. Numerous chromosomal alterations have been observed in ACCs, and they are much more frequent than in adrenocortical adenomas. Progress in the genetics of familial syndromes associated with ACTs helped to identify significant somatic molecular alterations in sporadic adult ACCs. Somatic mutations of the tumour suppressor gene TP53 are observed in a third of ACCs. Interestingly, allelic losses (LOH) at the TP53 locus (17p13) are very frequent, observed in more than 85% of ACCs. The insulin-like growth factor II (IGF-II) locus (11p15) is imprinted. IGF-II is over-expressed in 90% of ACCs. Transcriptome studies have identified an IGF-II cluster of genes significantly over-expressed in ACCs. Transcriptome analysis suggests also that the Wnt/beta-catenin signalling pathway is activated in ACT. About a third of ACCs harbours somatic activating mutations of the beta-catenin gene. This recent progress in the molecular genetics of ACC has led to the development of new molecular markers for the diagnosis of malignancy; these might also help to identify prognostic markers of ACC and may ultimately lead to novel therapeutic approaches.
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PMID:Pathogenesis of adrenocortical cancer. 1950 Jul 68