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)

The molecular genetics of endocrine tumours is an area of great interest, due to the heterogeneity of endocrine tumour types, the association of hormone over-production in some cases, and the wide variation in tumour behaviour. Genes implicated fall into functional categories such as oncogenes, in which mutations tend to cause activation, and tumour suppressor genes, in which mutations lead to loss of function. Oncogenes include the receptor tyrosine kinases such as RET, signal transduction proteins and other molecules such as cell cycle regulators and nuclear proteins. Tumour suppressor genes include cell cycle regulators such as p53 and other molecules such as the MEN 1 gene. Loss of heterozygosity studies help in the initial localisation of the latter. Endocrine tumours, as with other tumours, develop as a result of a combination of genetic events, and in the paediatric age group they often occur in the setting of familial cancer syndromes. In this review we analyse the main genetic lesions which have been described in endocrine tumours. There has been an explosion of knowledge in the last 5 years including the identification of the causative genes for MEN 2 and most recently for MEN 1. Characterisation of such genes also aids in the study of somatic mutations in sporadic versions of the same tumour types as occur in the familial syndromes. Identification of a genetic predisposition to a certain tumour has management implications that are still to be clarified in most cases, although in the case of MEN 2 the guidelines for prophylactic thyroidectomy are generally well accepted.
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PMID:The molecular genetics of endocrine tumours. 964 36

Tumour suppressor genes may have a role in the control of trophoblast cell population expansion as trophoblast invasion occurs. To investigate this hypothesis, the location of tumour suppressor gene and proto-oncogene products were studied at various stages of trophoblast differentiation and invasion. Trophoblast and decidua were obtained from eight women having a therapeutic termination of pregnancy. Immunohistochemistry was used to localize the products of c-myc, c-erB-2, RB, BCL-2, P21, and P53 genes and anti-cytokeratin was used to identify fetal cells amongst the maternal decidual cells. The most differentiated and furthest invading trophoblast cell type, the multinucleated trophoblast, expressed a combination of genes which may indicate a high apoptotic rate. The other fully differentiated trophoblast, the syncytiotrophoblast, expressed BCL-2 suggesting protection from apoptosis. The co-occurrence of proto-oncogenes and the products of tumour suppressor genes in first trimester trophoblast suggests an important role not only in negative regulation of cellular invasion but also in population expansion through the presence of oncogenes and anti-apoptotic proteins.
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PMID:Oncogene and tumour suppressor gene products during trophoblast differentiation in the first trimester. 966 34

Von Hippel-Lindau disease (VHL) is caused by germline mutations in the VHL tumour suppressor gene. Tumour development in this setting is due to loss or inactivation of the remaining wild-type VHL allele. The VHL gene product (pVHL) resides primarily in the cytoplasm. A frequently mutated region of pVHL can bind to complexes containing elongin B, elongin C and Cul2. Loss of pVHL leads to an inappropriate accumulation of hypoxia-inducible mRNAs, such as the mRNA encoding vascular endothelial growth factor (VEGF), under normoxic conditions. This finding is most likely to account for the hypervascular nature of VHL-associated neoplasms. Current studies are focussed on understanding if and how binding to elongins and Cul2 is linked to the ability of pVHL to regulate hypoxia-inducible mRNAs. In this regard, it is perhaps noteworthy that elongin C and Cul2 are homologous to yeast proteins Skp1 and Cdc53. These latter proteins participate in the formation of complexes that target certain proteins for ubiquitination.
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PMID:Functions of the von Hippel-Lindau tumour suppressor protein. 968 55

The cyclin-dependent kinases 4 and 6 (Cdk4/6) that control the G1 phase of the cell cycle and their inhibitor, the p16INK4a tumour suppressor, have a central role in cell proliferation and in tumorigenesis. The structures of Cdk6 bound to p16INK4a and to the related p19INK4d reveal that the INK4 inhibitors bind next to the ATP-binding site of the catalytic cleft, opposite where the activating cyclin subunit binds. They prevent cyclin binding indirectly by causing structural changes that propagate to the cyclin-binding site. The INK4 inhibitors also distort the kinase catalytic cleft and interfere with ATP binding, which explains how they can inhibit the preassembled Cdk4/6-cyclin D complexes as well. Tumour-derived mutations in INK4a and Cdk4 map to interface contacts, solidifying the role of CDK binding and inhibition in the tumour suppressor activity of p16INK4a.
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PMID:Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a. 975 Oct 50

Although it is well known that oncogenesis is a multistep process involving the activation of normal cellular genes to become oncogenes and/or the inactivation of tumor suppressor genes, this process has seldom been investigated in soft tissue tumours. We screened a group of 36 liposarcomas for genetic abnormalities in the p53 tumour suppressor gene and c-myc oncogene. Altered c-myc gene expression was examined by differential RT-PCR assay. p53 Gene mutations in exons 4-8 were analysed by using PCR-SSCP analysis and direct sequencing. Elevated c-myc expression was found in 6 of 31 liposarcomas (19.4%). p53 Gene mutations were observed in 5 of 36 liposarcomas (13.9%). Both genetic alterations were associated with the histological subtype of liposarcomas. Whereas c-myc gene expression was a characteristic of myxoid/round cell liposarcomas, p53 gene mutations were found more frequently in pleomorphic variants. Liposarcomas of the well-differentiated subtype showed neither p53 gene mutations nor altered c-myc gene expression. Our results indicate that the c-myc oncogene and the p53 tumor suppressor gene do not seem to cooperate in the oncogenesis of liposarcomas.
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PMID:No correlation of c-myc overexpression and p53 mutations in liposarcomas. 980 33

Tumour suppressor genes prevent cancer development. They can be identified by studying humans, but a full understanding of the mechanisms of their action requires the production of animal models. Mice with mutations in tumour suppressor genes can be produced by gene targeting. The phenotypic consequences of tumour suppressor gene mutations in mice and humans show parallels and contrasts, and both can contribute to the elucidation of disease processes.
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PMID:Tumour suppressor gene mutations in humans and mice: parallels and contrasts. 984 83

Schwannomas are common benign tumours of schwann cell origin, frequently found in patients with neurofibromatosis type 2 (NF2). Inactivation of the NF2 tumour suppressor gene appears to be a molecular event responsible for the development of up to 60% of cases, but no data are available on other superimposed secondary or alternative molecular abnormalities in those schwannomas lacking NF2 gene inactivation. We analysed 23 sporadic schwannomas for mutations in the NF2 gene and for the allelic status at 1p, 14q and 22q, as alterations of these genomic regions appear to be related to tumour progression in meningiomas, another NF2-associated neoplasm. Nine samples displayed allelic losses for markers on chromosome 22, and deletions at 1p were detected in two. No case showed losses for 14q. Three tumours displayed NF2 gene mutations, at exons 2, 7 and 12. Our results confirm that inactivation of the NF2 gene is a primary event in schwannoma development, and provide data suggesting that allelic loss at 1p may contribute to the pathogenesis of a small subgroup of this histological tumour type.
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PMID:Allelic status of 1p, 14q, and 22q and NF2 gene mutations in sporadic schwannomas. 985 12

Ultraviolet (UV) radiation contributes to the aetiology of melanoma, but the precise mechanistic details are still unclear. The CDKN2A gene which is associated with familial and sporadic melanoma, encodes a tumour suppressor, p16. We have previously shown that in response to low doses of UV radiation the level of p16 increases, and that this correlates with a G2 delay. Here we report that in melanoma cell lines which do not express p16, or express a mutant p16, no G2 delay is observed in response to UV. The loss of functional p16 also correlates with an increase in DNA damage as judged by increased numbers of bi- and multinuclear cells and cells containing 1-2 micronuclei following UV irradiation. This work provides a further link between UV radiation, CDKN2A and melanoma, suggesting that the functional inactivation of CDKN2A disrupts a p16-dependent G2 cell cycle checkpoint, thus contributing to the development of this neoplasm.
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PMID:Involvement of p16CDKN2A in cell cycle delays after low dose UV irradiation. 992 Apr 27

The activation of oncogenes and the inactivation of tumour suppressor genes play a critical role in laryngeal tumorigenesis. Recent investigations revealed that 8p, 9p and 17q arms of human chromosomes harbour tumour suppressor genes (TSGs) such as p16 and BRCA1 with an important role in the multistage carcinogenesis of the larynx. In order to investigate the implication of these novel TSGs in the development of laryngeal neoplasia we performed a loss of heterozygosity (LOH) analysis using a bank of 15 polymorphic microsatellite markers (4 at 8p21, 7 at 9p21 arm and 4 at 17q arm surrounding the BRCA1 region) in a series of 32 cytological specimens (19 squamous cell carcinoma, 13 benign lesions of the larynx). Both benign and malignant specimens exhibited genetic alterations with at least one microsatellite marker. Fifteen (47%) out of the 32 specimens exhibited LOH at 8p21, 25/32 (78%) showed LOH at 9p21 and 18/32 (56%) displayed LOH at 17q21. Genetic alterations were detected in both benign and malignant lesions for all the loci tested suggesting an important role of these regions in the development of laryngeal neoplasia. This is the first report of detection of microsatellite alterations not only in solid tumours of the larynx but in laryngeal cytological specimens, suggesting that microsatellite analysis may be a useful tool in the primary diagnosis of the disease.
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PMID:Loss of heterozygosity at 8p, 9p and 17q in laryngeal cytological specimens. 993 Mar 65

The tumour suppressor gene PTEN (also called MMAC1 or TEP1) is somatically mutated in a variety of cancer types [1] [2] [3] [4]. In addition, germline mutation of PTEN is responsible for two dominantly inherited, related cancer syndromes called Cowden disease and Bannayan-Ruvalcaba-Riley syndrome [4]. PTEN encodes a dual-specificity phosphatase that inhibits cell spreading and migration partly by inhibiting integrin-mediated signalling [5] [6] [7]. Furthermore, PTEN regulates the levels of phosphatidylinositol 3,4,5-trisphosphate (PIP3) by specifically dephosphorylating position 3 on the inositol ring [8]. We report here that the dauer formation gene daf-18 is the Caenorhabditis elegans homologue of PTEN. DAF-18 is a component of the insulin-like signalling pathway controlling entry into diapause and adult longevity that is regulated by the DAF-2 receptor tyrosine kinase and the AGE-1 PI 3-kinase [9]. Others have shown that mutation of daf-18 suppresses the life extension and constitutive dauer formation associated with daf-2 or age-1 mutants. Similarly, we show that inactivation of daf-18 by RNA-mediated interference mimics this suppression, and that a wild-type daf-18 transgene rescues the dauer defect. These results indicate that PTEN/daf-18 antagonizes the DAF-2-AGE-1 pathway, perhaps by catalyzing dephosphorylation of the PIP3 generated by AGE-1. These data further support the notion that mutations of PTEN contribute to the development of human neoplasia through an aberrant activation of the PI 3-kinase signalling cascade.
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PMID:Regulation of dauer larva development in Caenorhabditis elegans by daf-18, a homologue of the tumour suppressor PTEN. 1020 98


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