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)

Bladder cancers display different forms from superficial to aggressive tumours with muscle invasion. Many studies on this disease have been carried out in order to better understand the molecular mechanisms involved in its progression. Two loci are frequently associated with bladder tumorigenesis. The chromosome 9 lesions seem to be earlier involved in carcinogenesis, and suggest the presence of a tumour suppressor gene, and on the other hand the TP53 gene mutations (17q13.1) are later but take place in tumour progression. These alterations could be used as early diagnosis tool in bladder tumours and orientate the search for the bladder cancer gatekeeper gene(s).
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PMID:[Tracking the gatekeeper gene in the stages of carcinogenesis in the bladder]. 943 99

T-prolymphocytic leukaemia (T-PLL) is a rare, sporadic leukaemia similar to a mature T-cell leukaemia seen in some patients with Ataxia Telangiectasia (A-T), a recessive multisystem disorder caused by mutations of the ATM gene at chromosome 11q23. ATM sequence mutations have been reported in 46% of T-PLL cases, but some cases also have karyotypic abnormalities at 11q, including 11q23. This led us to investigate the structure of the ATM locus in a panel of eight cases, two of which had 11q23 abnormalities. As expected, nucleotide changes were detected in some samples. Two remission samples were wild type. To test for structural lesions, DNA fibres were hybridized with a contig of four labelled cosmids spanning the ATM locus. In all samples there were structural lesions and in four samples both alleles were affected. This provides strong evidence for our suggestion that ATM acts as a tumour suppressor during T-PLL tumorigenesis. Some additional role for ATM during T-PLL tumorigenesis is possible since nucleotide changes were present in addition to structural lesions disrupting both alleles. The mechanism of inactivation appeared to be unusual because multiple structural lesions on one allele were often observed.
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PMID:ATM is usually rearranged in T-cell prolymphocytic leukaemia. 948 43

Cytogenetic and molecular analyses of primary sporadic human breast carcinomas have documented at least 12 different chromosome arms affected by loss of heterozygosity (LOH). This has been taken as evidence for the presence of putative tumour suppressor genes in the remaining allele within the affected regions. We have previously identified three regions on chromosome 17q that are affected by LOH in primary human breast tumours. A physical map of one of these regions (17q21) has been prepared. The putative target gene appears to be located between the D17S846 and D17S746 loci. We are currently determining whether either of two genes located in this region is the target for LOH. The mouse mammary tumour model system provides an approach for identifying genes which, when activated or inactivated by mouse mammary tumour virus (MMTV) integration, contribute to specific stages of mammary tumorigenesis. Using this approach we have identified two genes, designated NOTCH4/INT3 and INT6 respectively. Interruption of NOTCH4/INT3 by MMTV represents a gain-of-function mutation that has profound consequences for mammary gland development and tumorigenesis. INT6 was found to be interrupted by an integrated MMTV genome in a mammary hyperplastic outgrowth line and two independent mammary tumours. In each case the transcriptional orientation of the viral genome was opposite to that of INT6. The rearranged allele was expressed as a truncated chimaeric RNA species composed of INT6 coding sequences, intron sequences and MMTV sequences. Since the non-rearranged allele contained no mutations, we conclude that MMTV integration into INT6 causes a dominant-negative mutation or biologically activates its function. The nucleotide sequence of INT6 is unrelated to any of the known genes in the GenBank database, but is evolutionarily highly conserved.
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PMID:Somatic mutations that contribute to breast cancer. 951 25

Neuroblastoma has several clinical and molecular genetic parallels with the other paediatric embryonal tumours, such as retinoblastoma, including a hereditary form of the disease. We hypothesised that neuroblastoma susceptibility is due to germline mutations in a tumour suppressor gene and that this predisposition gene may be involved in sporadic neuroblastoma tumorigenesis as well. We therefore aimed to localise the familial neuroblastoma predisposition gene by linkage analysis in neuroblastoma kindreds. Eighteen families segregating for neuroblastoma were ascertained for candidate locus linkage analysis. Although many of the 49 affected individuals in these families were diagnosed as infants with multifocal primary tumours, there was marked clinical heterogeneity. We originally hypothesised that familial neuroblastoma predisposition would map to the telomeric portion of chromosome band 1p36, a genomic region likely to contain a sporadic neuroblastoma suppressor gene. However, neuroblastoma predisposition did not map to any of eight polymorphic markers spanning 1p36.2-.3 in three large kindreds. In addition, there was strong evidence against linkage to two Hirschsprung disease susceptibility genes (RET and EDNRB), a condition that can cosegregate with neuroblastoma as in one of the kindreds tested here. We conclude that the neuroblastoma susceptibility gene is distinct from the 1p36 neuroblastoma suppressor and two of the currently identified Hirschsprung disease susceptibility genes.
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PMID:Molecular genetic analysis of familial neuroblastoma. 951 25

The second joint conference of the AACR and the EACR held in Oxford from 9-12 September 1997 was successful from many vantage points. While providing an optimal setting in which European and American cancer researchers could meet and exchange information, the conference had an excellent scientific programme which encompassed both methodological updates on important models used in cancer research and presentations of recent key advances in the molecular genetics of cancer. Lower eukaryotes are established model organisms used to elucidate fundamental but complex eukaryotic processes, such as those involved in tumorigenesis and cancer progression, and the progressive availability of their genome sequence makes them even more attractive. Transgenic mouse models are increasingly used not only for the study of one gene of interest but for investigation of the interactions among genes involved in the same pathway. The family of tumour suppressor genes is growing fast and several presentations were devoted to recently identified members such as the Von Hippel-Lindau gene, the FHIT gene and the PTEN gene. The systematic analysis of loss of heterozygosity on multiple loci in tumour specimens can provide the basis for preliminary models of molecular multistep progression in some tumour types, even though this is limited by the high degree of complexity found. Mechanisms of cell cycle regulation and apoptosis continue to be dissected and to constitute a fruitful area of investigation, with important recent insights on the p53-MDM2 autoregulatory loop and on the involvement of E2F-1 in apoptosis.
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PMID:Recent advances in the molecular genetics of cancer. Second joint conference of the American Association of Cancer Research and the European Association of Cancer Research, Oxford, 9-12 September 1997. 954 79

Although the mechanism remains obscure, two histological subtypes of gastric carcinoma (GC), the diffuse and intestinal types, differ drastically in epidemiological, clinical, pathological and biological characteristics. We investigated whether the genetic alterations of several oncogenes and tumour suppressor genes could be correlated with the two histological subtypes. In 60 patients with GC, the overexpression of mutant p53 and c-erbB-2 oncoproteins was studied using immunohistochemical stains. Mutations of the p15 and p16 tumour suppressor genes were assessed by polymerase chain reaction, Southern blotting, and direct DNA sequencing. Overexpression of c-erbB-2 and p53 was found in 21 (35.0%) and 27 (45.0%) patients, respectively. Overexpression of the c-erbB-2 oncoprotein was more common in the intestinal type (15/32, 46.9%) and the advanced stage (19/45, 42.2%) than in the diffuse type (6/28, 21.4%) and the early stage (2/15, 13.3%) of GC (P<0.05). Similarly, p53 overexpression was more frequently found in the intestinal type (19/32, 59.4%) and the advanced stage (24/45, 53.3%) than in the diffuse type (8/28, 28.6%) and the early stage (3/15, 20.0%) of GC (P<0.05). Homozygous deletions of p16 in exon 1 were found in six (10.0%) patients. Five of them had the intestinal-type advanced GC. Neither point mutations of p16 nor alterations of p15 were detected. The frequency of alterations of p53, c-erbB-2, and p16 was not related to sex and Helicobacter pylori infection. No correlation of genetic changes between any two genes was observed. Our preliminary results indicate alterations in the p15 gene were not important in gastric tumorigenesis, while infrequent homozygous deletions in the p16 gene play a limited role in tumour progression of intestinal-type GC. Moreover, overexpression of c-erbB-2 and p53 is frequently encountered in the intestinal-type advanced GC. Alterations of p53, c-erbB-2 and p16 genes may function independently of each other in gastric carcinogenesis. The association between genetic alterations and histological subtypes supports the notion that a distinct pathogenesis may exist in different histological subtypes.
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PMID:Overexpression of mutant p53 and c-erbB-2 proteins and mutations of the p15 and p16 genes in human gastric carcinoma: with respect to histological subtypes and stages. 957 Feb 45

Deletions involving chromosome 10q23 occur frequently in prostatic carcinomas. Recently, a novel tumour suppressor gene, PTEN, mapping to this interval, has been identified. Mutation or deletion of PTEN has been observed in a proportion of prostate cancer cell lines; however, primary prostate carcinomas have not been studied. We have investigated the involvement of PTEN in primary prostatic adenocarcinomas using a panel of 51 matched normal and prostate tumour DNAs. We first determined the proportion of tumours with allele loss at loci in 10q23 which span the region containing the PTEN gene. Our results show that LOH involving 10q23 is common in primary prostate carcinomas. Twenty-five of 51 (49%) tumours showed loss of heterozygosity (LOH) over the region spanning the PTEN locus. We next directly analysed the PTEN gene for mutations of the coding region using single strand conformation polymorphism (SSCP) and sequence analyses. Of those tumours with LOH, only a single tumour was found to carry a missense mutation in PTEN. No mutations in PTEN were identified in tumours without LOH. Our results suggest either that mutation of PTEN is a late event in prostate tumorigenesis, or that another tumour suppressor gene important in prostate cancer may lie close to PTEN in 10q23.
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PMID:Analysis of PTEN and the 10q23 region in primary prostate carcinomas. 958 22

Bax suppresses tumorigenesis in a mouse model system and Bax-deficient mice exhibit lymphoid hyperplasia suggesting that BAX functions as a tumour suppressor in human haemopoietic cells. We examined BAX expression in 20 cell lines derived from human haemopoietic malignancies and consistent with a potential tumour suppressor function, identified two cell lines, DG75 (a Burkitt lymphoma cell line) and Jurkat (a T-cell leukaemia line), which lacked detectable BAX expression. Apoptosis of DG75 cells induced by low serum or ionomycin was significantly delayed relative to similar Burkitt lymphoma cell lines with normal BAX levels. Although DG75 and Jurkat cells expressed several BAX RNA species including the prototypical BAX alpha RNA, the absence of BAX protein was due to single base deletions and additions in a polyguanine tract within the BAX open reading frame. These frameshift mutations result in premature termination of translation and have recently also been identified in some colon cancers with microsatellite instability. Although mismatch repair defects are not considered a common feature of haemopoietic malignancies, DG75 and Jurkat cells had widespread microsatellite instability and did not express detectable levels of MSH2. In Jurkat cells, lack of MSH2 expression was due to a point mutation in exon 13 of MSH2 resulting in premature termination of translation. Our results suggest that a pathway linking mismatch repair defects, BAX tumour suppressor frameshift mutations and resistance to apoptosis may be a key feature of some lymphomas and leukaemias.
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PMID:BAX frameshift mutations in cell lines derived from human haemopoietic malignancies are associated with resistance to apoptosis and microsatellite instability. 958 78

Mxi1 belongs to the Mad (Mxi1) family of proteins, which function as potent antagonists of Myc oncoproteins. This antagonism relates partly to their ability to compete with Myc for the protein Max and for consensus DNA binding sites and to recruit transcriptional co-repressors. Mad(Mxi1) proteins have been suggested to be essential in cellular growth control and/or in the induction and maintenance of the differentiated state. Consistent with these roles, mxi1 may be the tumour-suppressor gene that resides at region 24-26 of the long arm of chromosome 10. This region is a cancer hotspot, and mutations here may be involved in several cancers, including prostate adenocarcinoma. Here we show that mice lacking Mxi1 exhibit progressive, multisystem abnormalities. These mice also show increased susceptibility to tumorigenesis either following carcinogen treatment or when also deficient in Ink4a. This cancer-prone phenotype may correlate with the enhanced ability of several mxi1-deficient cell types, including prostatic epithelium, to proliferate. Our results show that Mxi1 is involved in the homeostasis of differentiated organ systems, acts as a tumour suppressor in vivo, and engages the Myc network in a functionally relevant manner.
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PMID:Role of Mxi1 in ageing organ systems and the regulation of normal and neoplastic growth. 962 6

Malignant rhabdoid tumours (MRTs) are extremely aggressive cancers of early childhood. They can occur in various locations, mainly the kidney, brain and soft tissues. Cytogenetic and molecular analyses have shown that the deletion of region 11.2 of the long arm of chromosome 22 (22q11.2) is a recurrent genetic characteristic of MRTs, indicating that this locus may encode a tumour suppressor gene. Here we map the most frequently deleted part of chromosome 22q11.2 from a panel of 13 MRT cell lines. We observed six homozygous deletions that delineate the smallest region of overlap between the cell lines. This region is found in the hSNF5/INI1 gene, which encodes a member of the chromatin-remodelling SWI/SNF multiprotein complexes. We analysed the sequence of hSNF5/INI1 and found frameshift or nonsense mutations of this gene in six other cell lines. These truncating mutations of one allele were associated with the loss of the other allele. Identical alterations were observed in corresponding primary tumour DNAs but not in matched constitutional DNAs, indicating that they had been acquired somatically. The observation of bi-allelic alterations of hSNF5/INI1 in MRTs suggests that loss-of-function mutations of hSNF5/INI1 contribute to oncogenesis.
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PMID:Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. 967 7


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