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)

Ataxia-telangiectasia (A-T) is a recessive multi-system disorder caused by mutations in the ATM gene at 11q22-q23 (ref. 3). The risk of cancer, especially lymphoid neoplasias, is substantially elevated in A-T patients and has long been associated with chromosomal instability. By analysing tumour DNA from patients with sporadic T-cell prolymphocytic leukaemia (T-PLL), a rare clonal malignancy with similarities to a mature T-cell leukaemia seen in A-T, we demonstrate a high frequency of ATM mutations in T-PLL. In marked contrast to the ATM mutation pattern in A-T, the most frequent nucleotide changes in this leukaemia were missense mutations. These clustered in the region corresponding to the kinase domain, which is highly conserved in ATM-related proteins in mouse, yeast and Drosophila. The resulting amino-acid substitutions are predicted to interfere with ATP binding or substrate recognition. Two of seventeen mutated T-PLL samples had a previously reported A-T allele. In contrast, no mutations were detected in the p53 gene, suggesting that this tumour suppressor is not frequently altered in this leukaemia. Occasional missense mutations in ATM were also found in tumour DNA from patients with B-cell non-Hodgkin's lymphomas (B-NHL) and a B-NHL cell line. The evidence of a significant proportion of loss-of-function mutations and a complete absence of the normal copy of ATM in the majority of mutated tumours establishes somatic inactivation of this gene in the pathogenesis of sporadic T-PLL and suggests that ATM acts as a tumour suppressor. As constitutional DNA was not available, a putative hereditary predisposition to T-PLL will require further investigation.
Nat Genet 1997 Sep
PMID:Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia. 928 6

Deletions and translocations of 13q14 are the most frequent structural chromosome abnormalities found in chronic lymphocytic leukaemia (CLL). We have identified 13q14 translocations in the blood of 30 of 450 (6.6%) CLL patients by conventional cytogenetics, using tetradecanoyl phorbol 12-myristate 13-acetate (TPA) as a mitogen. The translocations are characterised by multiple partner chromosomes and a high incidence, 6 of 30 cases, of complex rearrangements. Seven cases were also studied by fluorescence in situ hybridisation (FISH) using four previously ordered YACs, to define the breakpoints further. Deletions with varying proximal and distal breakpoints were found in six cases. Two of the cases had deletions of the cytogenetically normal chromosome 13 at q14, and in one case the 13q14 translocation was a secondary genetic event. No difference in the clinical features between the patients with 13q14 translocation and 54 patients with 13q14 deletions or four patients with both a translocation and a deletion was observed. These data suggest that the genetic consequence of 13q14 translocations in CLL is the loss of a tumour suppressor gene.
Genes Chromosomes Cancer 1997 Sep
PMID:Cytogenetic, fluorescence in situ hybridisation, and clinical evaluation of translocations with concomitant deletion at 13q14 in chronic lymphocytic leukaemia. 929 Sep 57

The tumour suppressor protein p53 is expressed at very low levels in normal cells but accumulates in response to DNA damaging agents such as u.v. irradiation. This increase is accompanied by transcriptional upregulation of the expression of a number of proteins including Mdm2 which can in turn inhibit p53 dependent transcriptional activation, creating a feedback loop resulting in down-regulation of p53 activity. Mutant p53 proteins are however frequently detected at constitutively high levels in many tumours and tumour cell lines, indeed this phenomenon has been used in several studies to diagnose p53 mutation in patient tumours. We show here that expression of mouse mutant p53 in tumour cell lines of this type results in high levels of both the endogenous p53 protein and the exogenously expressed mutant mouse protein, whereas the human tumour line MCF7 does not exhibit high levels of either endogenous human or exogenously expressed mouse mutant p53 unless stabilisation is induced by DNA damage. This suggests that the stability of mutant p53 is not intrinsic to mutant p53 protein structure but may vary in different cell backgrounds. We present evidence that p53 protein stability in tumour cell lines is determined by association with the Mdm2 tumour suppressor protein, and that p53 mutants which are unable to bind Mdm2 are stable in MCF7 cells. We propose that tumour lines which express high levels of transcriptionally inactive mutant p53 are unable to induce the expression of the Mdm2 protein which would normally provide a feedback mechanism down-regulating p53 protein levels in the absence of DNA damage signals. MCF7 cells however express a transcriptionally active p53 and retain the feedback regulation of p53 protein levels by Mdm2.
Oncogene 1997 Sep 04
PMID:p53 protein stability in tumour cells is not determined by mutation but is dependent on Mdm2 binding. 929 11

Membrane dipeptidase (MDP) is a zinc metalloenzyme located in the lungs and on the brush border membranes of the kidney and intestine. The gene for MDP (also termed DPEP1) is both frequently lost in Wilm's tumours and is located on human chromosome 16q24.3, a region of the genome known to contain a tumour suppressor gene(s). We now report on the regulation of MDP gene expression in normal and transformed cells. MDP enzyme activity and mRNA was detected in primary baby rat kidney (BRK) cells maintained in culture for up to 4 weeks. In contrast all stable transformed cell lines that were tested, derived either by transformation with the DNA tumour viruses SV40 or adenovirus, or in human tumour cell lines, contained very low levels of or no detectable MDP mRNA or enzyme activity. In BRK cells transformed by the temperature-sensitive tsA58 mutant of SV40 T antigen, MDP activity was not detectable, in cell lines grown at the permissive temperature (33 degrees C) but after 5-14 days of incubation at the non-permissive temperature (39.5 degrees C), MDP protein and enzyme activity could be readily detected. Taken together, these results indicate that MDP expression is characteristic of differentiated kidney epithelial cells and is down-regulated in proliferating, transformed cells.
Oncogene 1997 Sep 04
PMID:Stable and temperature-sensitive transformation of baby rat kidney cells by SV40 suppresses expression of membrane dipeptidase. 929 18

The protein p53 is the most frequently mutated tumour suppressor to be identified so far in human cancers. The ability of p53 to inhibit cell growth is due, at least in part, to its ability to bind to specific DNA sequences and activate the transcription of target genes such as that encoding the cell-cycle inhibitor p21Waf1/Cip1 . A gene has recently been identified that is predicted to encode a protein with significant amino-acid sequence similarity to p53. In particular, each of the p53 amino-acid residues implicated in direct sequence-specific DNA binding is conserved in this protein. This gene, called p73, maps to the short arm of chromosome 1, and is found in a region that is frequently deleted in neuroblastomas. Here we show that p73 can, at least when overproduced, activate the transcription of p53-responsive genes and inhibit cell growth in a p53-like manner by inducing apoptosis (programmed cell death).
Nature 1997 Sep 11
PMID:p73 is a simian [correction of human] p53-related protein that can induce apoptosis. 929 83

The most common tumour suppressor gene altered in human cancers is p53, which is located on the short arm of chromosome 17. Structural abnormalities of the short arm and loss of chromosome 17 have been reported to confer resistance to chemotherapy in patients with non-Hodgkin's lymphoma (NHL). Therefore we studied the incidence and prognostic value of p53 deletions in patients with NHL by fluorescence in-situ hybridization using a 40 kb cosmid probe. Specimens obtained from 79 patients with NHL were studied. 46 patients were untreated, and 33 were previously treated. 40 tumours had indolent and 39 had aggressive histologies. p53 deletions were observed in 14 specimens (18%) in 32-90% of the cells. No statistically significant difference in the incidence of p53 deletion was observed between indolent and aggressive NHLs or between untreated and previously treated patients. However, p53 deletions were observed in three of four patients with transformed lymphoma. In the untreated patients, p53 deletion had no effect on response to therapy, time to treatment failure, or survival. We conclude that p53 deletions are uncommon in NHL, and may be frequent in patients with transformed lymphoma. In this study, p53 deletions did not influence treatment outcome or prognosis of NHL. Because monosomy 17 and 17p abnormalities have been reported to confer poor prognosis in NHL, other tumour suppressor genes on 17p should therefore be studied.
Br J Haematol 1997 Sep
PMID:Analysis of p53 gene deletions in patients with non-Hodgkin's lymphoma by dual-colour fluorescence in-situ hybridization. 932 89

We examined the effect of the stable transfection of latent TGF-beta 1 cDNA, under the control of a cytomegalovirus promoter in the expression vector pcDNA3, into a 4NQO-induced clonal rat oral keratinocyte cell line that formed undifferentiated spindle cell tumours following subcutaneous transplantation to athymic mice. Test cells containing latent TGF-beta 1 cDNA produced a 2.3-fold increase in TGF-beta 1 protein compared to pcDNA3 controls as demonstrated by ELISA. Neutralisation experiments indicated that the majority of the protein was in the latent form. Untransfected and transfected (containing either TGF-beta 1 cDNA or pcDNA3) cell lines were keratin negative and vimentin positive. Cells transfected with TGF-beta 1 were inhibited more than pcDNA3 controls when cultured in an anchorage dependent or independent environment. Subcutaneous transplantation of cells overproducing TGF-beta 1 resulted in tumours of significantly smaller volume than vector-only controls. Further, orthotopic transplantation of cells containing TGF-beta 1 cDNA to the floor of the mouth in athymic mice markedly inhibited the development of pulmonary metastases compared to vector-only controls. Both test and control cell lines in athymic mice formed undifferentiated tumours with a complete absence of keratin elaboration. Subcutaneous xenografts were recultured and cells containing the TGF-beta 1 cDNA produced a similar amount of TGF-beta 1 peptide as the cells containing pcDNA3 only. The production of TGF-beta 1 by both of the xenograft-derived cell lines was significantly less than the parent, pre-transplanted cell lines and the untransfected cell line. All of the cell lines were inhibited by exogenous TGF-beta 1. Our results demonstrate that autocrine TGF-beta 1 functions as a tumour suppressor in vitro and in vivo in 4NQO-induced spindle tumour cells that are growth inhibited by the ligand. Furthermore, tumour formation in athymic mice is associated with selection for a cell phenotype with diminished autocrine TGF-beta 1 production.
Int J Cancer 1997 Sep 26
PMID:Overexpression of autocrine TGF-beta 1 suppresses the growth of spindle epithelial cells in vitro and in vivo in the rat 4NQO model of oral carcinogenesis. 933 12

Loss of DNA mismatch repair has been described in a number of tumour types such as colorectal adenocarcinoma and leads to microsatellite instability. This may have clinical relevance due to mismatch repair defects altering chemosensitivity towards certain classes of anti-tumour agent. This study has examined microsatellite instability of eight murine colon adenocarcinoma tumour models induced by 1,2-dimethylhydrazine. Four microsatellite regions were examined suggesting that four of the tumour models exhibit a low level of microsatellite instability. Loss of heterozygosity was found in 5/8 tumours, suggesting that allelic loss may be a relatively common step in the carcinogenesis of these tumour models. Three of the allelic losses involved the D11MIT4 locus which is situated very close to the p53 tumour suppressor locus. Four tumour models are routinely cultured in vitro and these were used to examine whether there was any association between microsatellite instability, mutant frequency and chemo-sensitivity of these tumour models, comparing them with four human adenocarcinoma cell lines of known mismatch repair status. Two cell lines (MAC26 and MAC16) were found to be more chemoresistant towards cisplatin but not 6-thioguanine. No association was found between microsatellite instability and chemosensitivity for either the human or mouse cell lines.
Int J Oncol 1998 Sep
PMID:Microsatellite instability, chemosensitivity and mutant frequency in a series of 1,2-dimethylhydrazine induced murine colon adenocarcinoma models. 968 89

The two distinct proteins encoded by the CDKN2A locus are specified by translating the common second exon in alternative reading frames. The product of the alpha transcript, p16(INK4a), is a recognized tumour suppressor that induces a G1 cell cycle arrest by inhibiting the phosphorylation of the retinoblastoma protein by the cyclin-dependent kinases, CDK4 and CDK6. In contrast, the product of the human CDKN2A beta transcript, p14(ARF), activates a p53 response manifest in elevated levels of MDM2 and p21(CIP1) and cell cycle arrest in both G1 and G2/M. As a consequence, p14(ARF)-induced cell cycle arrest is p53 dependent and can be abrogated by the co-expression of human papilloma virus E6 protein. p14(ARF) acts by binding directly to MDM2, resulting in the stabilization of both p53 and MDM2. Conversely, p53 negatively regulates p14(ARF) expression and there is an inverse correlation between p14(ARF) expression and p53 function in human tumour cell lines. However, p14(ARF) expression is not involved in the response to DNA damage. These results place p14(ARF) in an independent pathway upstream of p53 and imply that CDKN2A encodes two proteins that are involved in tumour suppression.
EMBO J 1998 Sep 01
PMID:The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. 972 36

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.
Nature 1998 Sep 17
PMID:Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a. 975 Oct 50


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