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)

Forty early stage malignant and seven borderline ovarian tumours were analysed for loss of heterozygosity (LOH) on chromosomes 6, 7, 9, 11 and 17. LOH involving at least one locus was observed in 32 (80%) early stage and six (86%) borderline tumours. Frequent LOH in the early stage tumours was detected on chromosome arms 7p (31%), 7q (50%), 9p (42%) and 11q (34%) suggesting that these chromosomes harbour tumour suppressor genes which are inactivated early in tumorigenesis. Borderline tumours exhibited a similar pattern of LOH to that observed in the early stage malignant tumours, indicating that the development of both malignant and borderline forms may involve inactivation of the same set of tumour suppressor genes. Together with our previous investigation of benign ovarian tumours this data supports the theory that malignant ovarian tumours may arise from benign and borderline precursors.
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PMID:Loss of heterozygosity on chromosomes 7p, 7q, 9p and 11q is an early event in ovarian tumorigenesis. 967 5

For nearly a decade since the mapping of the multiple endocrine neoplasia type 1 (MEN1) locus to 11q13 and the suggestion that it is a tumour suppressor gene, efforts have been made to identify the gene responsible for this familial cancer syndrome. Recently, we have identified the MEN1 gene by the positional cloning approach. This effort involved construction of a 2.8-Mb physical map (D11S480-D11S913) based primarily on a bacterial clone contig. Using these resources, 20 new polymorphic markers were isolated which helped to reduce the interval for candidate genes by haplotype analysis in families and by loss of heterozygosity (LOH) studies in approximately 200 tumours, utilizing laser-assisted microdissection to obtain tumour cells with minimal or no admixture by normal cells. The interval was narrowed by LOH to only 300 kb, and nearly 20 new transcripts that map to this region of 11q13 were isolated and characterized. One of the transcripts was found by dideoxyfingerprinting and cycle sequencing to harbour deleterious germline mutations in affected individuals from MEN-1 kindreds and therefore identified as the MEN1 gene. The type of germline mutations and the identification of mutations in sporadic tumours support the Knudson's two-hit model of tumorigenesis for MEN-1. Efforts are being made to identify the function of the MEN1 gene-encoded protein, menin, and to study its role in tumorigenesis.
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PMID:Identification and characterization of the multiple endocrine neoplasia type 1 (MEN1) gene. 968 40

The cells populating the intestinal crypts are part of a dynamic tissue system which involves the self-renewal of stem cells, a commitment to proliferation, lineage-specific differentiation, movement and cell death. Our knowledge of these processes is limited, but even now there are important clues to the nature of the regulatory systems, and these clues are leading to a better understanding of intestinal cancers. Few intestinal-specific markers have been described; however, homeobox genes such as cdx-2 appear to be important for morphogenic events in the intestine. There are several intestinal cell surface proteins such as the A33 antigen which have been used as targets for immunotherapy. Many regulatory cytokines (lymphokines or growth factors) influence intestinal development: enteroglucagon, IL-2, FGF, EGF family members. In conjunction with cell-cell contact and/or ECM, these cytokines lead to specific differentiation signals. Although the tissue distribution of mitogens such as EGF, TGF alpha, amphiregulin, betacellulin, HB-EGF and cripto have been studied in detail, the physiological roles of these proteins have been difficult to determine. Clearly, these mitogens and the corresponding receptors are involved in the maintenance and progression of the tumorigenic state. The interactions between mitogenic, tumour suppressor and oncogenic systems are complex, but the tumorigenic effects of multiple lesions in intestinal carcinomas involve synergistic actions from lesions in these different systems. Together, the truncation of apc and activation of the ras oncogene are sufficient to induce colon tumorigenesis. If we are to improve cancer therapy, it is imperative that we discover the biological significance of these interactions, in particular the effects on cell division, movement and survival.
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PMID:Growth control mechanisms in normal and transformed intestinal cells. 968 87

Cytogenetic analysis of Wilms tumours (WT) have shown that abnormalities involving chromosome 7 occur in approximately 25% of tumours. In some cases, these abnormalities involve deletions of the short arm, and are seen as the sole cytogenetic change, strongly suggesting the presence of a tumour suppressor gene in this location. Since loss of heterozygosity (LOH) studies have been crucial in defining chromosomal regions involved in Wilms tumorigenesis, we have analysed 40 sporadic Wilms tumours using a panel of 10 microsatellite polymorphic markers distributed along the length of the chromosome arm. In our series, four tumours (10%) showed allelic loss for 7p markers which is twice the background rate of LOH in WT. The shortest common region of overlap of LOH was located between markers D7S517-D7S503 in band 7p21-15. In one tumour there was evidence for a homozygous, interstitial deletion at a locus within this region. These findings provide strong evidence for the existence of a tumour suppressor gene involved in Wilms tumorigenesis and defines the critical region of the chromosome involved.
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PMID:Loss of heterozygosity for the short arm of chromosome 7 in sporadic Wilms tumour. 969 May 21

There is evidence that ovarian cancer may be derived from the progressive transformation of benign and/or borderline tumours. Mutations involving different oncogenes and tumour suppressor genes accumulate during the process of malignant transformation, and the alterations of genes involved in the pathogenesis of familial ovarian cancer are probably early events in ovarian tumorigenesis. BRCA-1 and BRCA-2 act as classical tumour suppressor genes in hereditary tumours, but their role in sporadic tumours remains controversial; however, a high frequency of allele losses in BRCA-1 (17q) and BRCA-2 (13q) loci has been observed in both familial and sporadic tumours. The possible role of mismatch repair genes and microsatellite instability is also controversial, but a role for them has been proposed in borderline tumours. Mutations in K-ras are specific for mucinous tumours and may be related to mucinous differentiation. Finally, a role in tumour progression has been proposed for both c-erb B-2 and p53, but their practical value in prognosis remains questionable.
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PMID:Molecular pathology of ovarian carcinomas. 973 87

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

Many chromosomal regions undergo loss of heterozygosity (LOH) in ovarian adenocarcinomas but few of the target regions have been finely mapped. One of the chromosome arms likely to harbour one or more tumour suppressor genes inactivated in ovarian cancer is the short arm of chromosome 8 which is frequently deleted in many other solid tumours. We have examined a large panel of microsatellite markers on 8p for LOH in 53 ovarian adenocarcinomas. LOH was observed in 27 tumours (51%), with a significant trend towards a higher frequency of LOH in more advanced tumours. Detailed examination of nine tumours with partial deletions defined three regions of overlap, two in 8p23 and one in 8p22, which suggests that there might be as many as three tumour or metastasis suppressor genes on 8p which are inactivated during ovarian tumorigenesis. LOH on 8p was significantly associated with 9p LOH which suggests that inactivation of target genes on these chromosomes may be cooperative events.
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PMID:Frequent loss of heterozygosity and three critical regions on the short arm of chromosome 8 in ovarian adenocarcinomas. 976 30

The PML gene of acute promyelocytic leukaemia (APL) encodes a cell growth and tumour suppressor, however, the mechanisms by which PML suppresses tumorigenesis are poorly understood. We show here that Pml is required for Fas- and caspase-dependent DNA-damage-induced apoptosis. We also found that Pml is essential for induction of programmed cell death by Fas, tumour necrosis factor alpha (TNF), ceramide and type I and II interferons (IFNs). As a result, Pml-/- mice and cells are protected from the lethal effects of ionizing radiation and anti-Fas antibody. Pml is required for caspase 1 and caspase 3 activation upon exposure to these stimuli. The PML-RAR alpha fusion protein of APL renders haemopoietic progenitor cells resistant to Fas-, TNF- and IFN-induced apoptosis with a lack of caspase 3 activation, thus acting as a Pml dominant-negative product. These results demonstrate that Pml is a mediator of multiple apoptotic signals, and implicate inhibition of apoptosis in the pathogenesis of APL.
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PMID:PML is essential for multiple apoptotic pathways. 980 33

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

p21waf1/cip1 protein, an inhibitor of cyclin dependent kinases, is a critical downstream target in the p53-specific pathway of growth control, and can also be induced by p53 independent pathways in relation to terminal differentiation. p21waf1 is also a putative tumour suppressor. Hence, we sought to determine whether this protein is abnormally expressed during betel- and tobacco-related oral oncogenesis. The aim was to determine whether a correlation exists between the expression profile of p21 and clinicopathological parameters of the patients, as well as with their p53 status. Immunohistochemical analysis showed that the expression of p21 protein in premalignant lesions was consistently elevated in the superficial, differentiated cells of the epithelium, while overexpression of the p53 tumour suppressor gene was observed in the basal proliferating layers of the epithelium. Our study demonstrated that p21 overexpression is associated with differentiation in proliferating dysplasias and squamous cell carcinomas (SCCs). The expression of p21 and p53 proteins was observed in 11/25 premalignant lesions. In 7 of these 11 cases, a heterogenous pattern of expression of p21 and p53 was observed. Four of these 11 premalignant and 30/51 malignant lesions showed concordant expression of both p21 and p53 proteins. The discordant p21 +/p53- phenotype was observed in 4/25 premalignant lesions and 5/51 oral SCCs. The p21-/p53+ phenotype was observed in 5/25 premalignant lesions and 7/51 oral SCCs. These results suggest that induction of p21 occurs by both p53 dependent and independent mechanisms during oral tumorigenesis.
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PMID:Expression of cyclin dependent kinase inhibitor p21waf1/cip1 in premalignant and malignant oral lesions: relationship with p53 status. 986 40


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