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 Wilms' tumour suppressor gene WT1 is essential for the normal development of the genitourinary system. It appears to play a role in both transcriptional and post-transcriptional regulation of certain cellular genes. However, the mechanisms behind WT1 function are not clearly understood despite the identification of numerous potential target genes and the isolation of several WT1-binding proteins. This study therefore sets out to identify other WT1-associating proteins to help to unravel how WT1 interacts with the cellular machinery. We report the identification of a novel human WT1-associating protein, WTAP, which was isolated using the yeast two-hybrid system. Both in vitro and in vivo assays have shown that the interaction between WTAP and WT1 is specific and occurs endogenously in cells. The mouse homologue of WTAP was isolated and found to be >90% conserved at the nucleotide and protein levels. The human and mouse genes were mapped using fluorescence in situ hybridization to regions in chromosomes 6 (which is thought to harbour a tumour suppressor gene) and 17, respectively. The expression pattern of WTAP was investigated and shown to be ubiquitous, perhaps reflecting a housekeeping role. WTAP is a nuclear protein, which like WT1 localizes throughout the nucleoplasm as well as in speckles and partially co-localizes with splicing factors. Although the significance of this interaction is not yet known, WTAP promises to be an interesting WT1-binding partner.
Hum Mol Genet 2000 Sep 22
PMID:Identification of WTAP, a novel Wilms' tumour 1-associating protein. 1100 26

P53 is extremely well characterised as a tumour suppressor gene, and many activities have been attributed to it which are consistent with this function. However, despite being the subject of intense study it still remains unclear precisely which of these functions is crucial to its in vivo role as a tumour suppressor gene. This is particularly true of its role in the induction of apoptosis. The original observation of p53-dependent apoptosis gave rise to the following hypothesis: namely, that p53 deficiency leads to a persistence of DNA damaged cells which are the potential founders of malignancy. This review summarises the data for and against this hypothesis, with specific emphasis on data obtained from studies of the murine intestine. What emerges from these studies is a complex picture, where data can be obtained in support of this hypothesis, but there are many circumstances which exist where it is not supported. Taken together this collection of data suggests that the abrogation of p53-dependent apoptosis may indeed impact upon carcinogenesis and neoplastic progression, but that the simplistic notion of p53 as the single gatekeeper of this pathway is untenable.
Mutat Res 2000 Sep 18
PMID:P53 null mice: damaging the hypothesis? 1102 75

It is now well established that oxidized LDL (OxLDL) is involved in the progression of the atheromatous plaque via several mechanisms, including its cytotoxicity toward the arterial wall. Our study demonstrates that a 4-h incubation of cultured human fibroblasts with 25-75 microg/ml OxLDL induced a dose-dependent increase in the intracellular levels of reactive oxygen species (ROS) and lipid peroxidation end products (TBARS). This effect was markedly prevented by the antioxidant vitamin E. The lipid extract of OxLDL partially reproduced the action of the LDL particle itself. Concomitantly, OxLDL enhanced the DNA binding activity of p53 measured by electrophoretic mobility shift assay, and the intracellular protein level of p53 determined by immunoblot analysis. Cycloheximide prevented the OxLDL-induced augmentation in both p53 binding activity and intracellular level. Again, the lipid extract of OxLDL reproduced the effect of OxLDL on p53 binding activity, whereas vitamin E prevented it. These results indicate that OxLDL initiates an intracellular oxidative stress by means of its lipid peroxidation products, leading to the activation of the tumour suppressor p53 by enhancement of p53 protein synthesis. This effect might be related to the cytotoxic effect of OxLDL since the activation of p53 is known to lead to cell cycle arrest, necrosis or apoptosis.
Biochem Biophys Res Commun 2000 Sep 24
PMID:Oxidized LDL induces an oxidative stress and activates the tumor suppressor p53 in MRC5 human fibroblasts. 1102 37

In childhood acute lymphoblastic leukaemia (ALL) a number of genetic changes have been identified which provide diagnostic and prognostic information with a direct impact on patient management. The most significant abnormalities include the translocation, t(12;21)(p13;q22), giving rise to the ETV6/AML1 gene fusion; BCR/ABL arising from t(9;22)(q34;q11); re-arrangements of the MLL gene; the E2A/PBX1 from the t(1;19)(q23;p13); re-arrangements of MYC with the immunoglobulin genes and re-arrangements of the T cell receptor genes. Chromosomal deletions, particularly those of the short arms of chromosomes 9 and 12 and the long arm of chromosome 6, have been postulated to be the sites of tumour suppressor genes (TSG). Numerical chromosomal abnormalities are of particular importance in relation to prognosis. High hyperdiploidy (50-65 chromosomes) is associated with a good risk, whereas the outlook for patients with near haploidy (23-29 chromosomes) is extremely poor. In view of the introduction of risk-adjusted therapy into the UK childhood ALL treatment trials, an interphase FISH screening programme has been developed to reveal chromosomal abnormalities with prognostic significance in childhood ALL.
Baillieres Best Pract Res Clin Haematol 2000 Sep
PMID:The genetics of childhood acute lymphoblastic leukaemia. 1103 43

T-cell prolymphocytic leukaemia (T-PLL) is a sporadic, mature T-cell disorder in which there is usually an aberrant T-cell receptor alpha (TCRA) rearrangement that activates the TCL1 or MTCP1-B1 oncogenes. As mutations of the Ataxia Telangiectasia (A-T) gene, ATM, are frequent in T-PLL and as ATM seems to act as a tumour suppressor through a mechanism involving V(D)J recombination, we examined V(D)J recombination in T-PLL. Using Southern blotting and the polymerase chain reaction, two of 60 TCRG coding joints were abnormal. In all cases, both TCRD alleles were deleted, IGH was germline, and patterns of TCRB and TCRA rearrangement were normal. However, in a case harbouring t(X;7)(q28;q35), we identified TCRB segment J beta 2.7 juxtaposed to MTCP1 exon 1. This is the first time that TCRB has been implicated in MTCP1 B1 activation. The structure of the breakpoint supports a model in which translocation activates a cryptic MTCP1 promoter. This analysis of V(D)J recombination is consistent with it being a variable that is independent of ATM in T-PLL.
Br J Haematol 2000 Sep
PMID:T-cell prolymphocytic leukaemia: antigen receptor gene rearrangement and a novel mode of MTCP1 B1 activation. 1105 65

Carbonic anhydrase (CA) IX and XII are transmembrane isoenzymes which are expressed in several epithelia and overexpressed in some carcinomas. They have recently been linked to von Hippel-Lindau gene-mediated carcinogenesis in that both isoenzymes are downregulated by the product of the wild-type von Hippel-Lindau tumour suppressor gene. This paper describes the localisation of CA IX and XII in the normal human pancreas and pancreatic tumours. Both isoenzymes showed positive reaction in the basolateral plasma membrane of the normal acinar and ductal epithelia. The hyperplastic ductal epithelium in tumour specimens generally showed an increased staining for CA IX. Of 29 malignant tumours of exocrine pancreas, 10 showed moderate or strong immunoreaction for CA IX. The signal for CA XII remained weak in most malignant lesions. The present results show that both CA IX and XII are unevenly expressed in the ductal and acinar compartments of the human pancreas. The expression of these isoenzymes in a relatively low number of malignant tumour specimens suggests that they have a limited value in diagnostic evaluation of pancreatic carcinoma. However, the increased expression of CA IX in hyperplastic ductal epithelium may contribute to the pancreatic tumourigenesis.
Histochem Cell Biol 2000 Sep
PMID:Expression of transmembrane carbonic anhydrase isoenzymes IX and XII in normal human pancreas and pancreatic tumours. 1108 62

In subgroups of astrocytic neoplasms, including glioblastoma (GBM), mutations of the p53 tumour suppressor gene lead to loss of growth-suppressive properties. A p53-related gene termed p73 has recently been identified; its gene product shows structural and functional similarities to p53. After being mapped to chromosome region 1p36, p73 was proposed to act as a tumour suppressor gene, as this region is frequently deleted in a variety of human cancers, including astrocytic tumours. To determine whether p73 is involved in astrocytoma/GBM development, we analysed 10 pilocytic astrocytomas, 15 WHO grade II astrocytomas, 15 WHO grade III anaplastic astrocytomas, and 20 GBM for p73 gene alterations. In parallel, we used six polymorphic markers to determine the allelic status of region 1p36 in this tumour series. Although loss of heterozygosity was evidenced in 12 of 60 cases (20% of samples), PCR-SSCP and direct sequencing failed to detect any gene mutation in the entire coding region and intronic sequences of p73. Eight tumours displayed five distinct polymorphic nucleotide changes, also present in the corresponding normal DNA. These variations consisted of T-->C variation, with no change in Thr173; C-->T transition, with no change in His197; exon 9 simultaneous double change C-->T and T-->C , with no variations in Ala336 and His349, respectively, and C-->T change at exon 9/-24 position of intron 8. These results suggest that, in astrocytic gliomas, p73 may not play a major role as a tumour suppressor, but the relatively high incidence of LOH confirms the presence at 1p36 of an as yet unidentified gene of this category, with a key function in astrocytoma/GBM progression.
Int J Oncol 2001 Sep
PMID:Absence of mutation of the p73 gene in astrocytic neoplasms. 1149 43

Giant cell tumours of bone (GCT) are characterized histologically by multinucleated bone resorbing giant cells in a background of ovoid spindle-shaped mesenchymal cells. Current evidence suggests that the latter comprise the tumour element of these lesions, although there are basic questions as to the factors that contribute to the tumourigenesis and progression of GCT. The deregulation of the p53/MDM2 pathway is an important pathogenetic event in many tumour types, prompting us to assess the expression of MDM2 by the stromal cells and giant cells of GCT. Northern blot analysis demonstrated that most of the GCT samples examined expressed increased levels of MDM2 when compared to normal human bone cells. However, Southern analysis failed to show any evidence of MDM2 gene amplification in the same samples, suggesting that increased levels of MDM2 mRNA were not a direct result of gene amplification, but rather due to altered transcriptional regulation of MDM2 gene. By RT-PCR analysis we found that 7/8 giant cell tumours expressed strongly a short alternatively spliced variant of MDM2, whereas other tumours of bone and normal human bone cells expressed predominantly full length MDM2. Sequence analysis confirmed this variant to be MDM2-b, a variant previously reported to confer a transformed phenotype. Cell fractionation of the GCTs has shown that the MDM2-b splice variant was expressed exclusively in the stromal population, whereas the full length MDM2 was expressed in the multinucleated giant cells of these lesions. Overexpression of a green fluorescent protein-tagged MDM2-b in human embryonic kidney cells (HEK-293), demonstrated predominantly nuclear localisation. Immunoprecipitation studies showed that MDM2-b is unable to physically associate with the p53 tumour suppressor protein. These results are consistent with the hypothesis that the stromal cells comprise the tumour element in giant cell tumours of bone and we speculate that expression of the MDM2-b splice variant contributes to their transformed phenotype in a p53 independent manner.
Int J Oncol 2001 Sep
PMID:Expression of alternatively-spliced MDM2 transcripts in giant cell tumours of bone. 1149 46

The development of multi-cellular organisms is regulated by the ordered definition of gene expression programmes that govern cell proliferation and differentiation. Although differential gene activity is mainly controlled by transcription factors, it is also dependent upon the underlying chromatin structure, which can stabilize transcriptional "on" or "off" states. We have recently isolated human (SUV39H1) and mouse (Suv39h1) histone methyltransferases (HMTases) and shown that they are important regulators for the organization of repressive chromatin domains. To investigate whether a SUV39H1-induced modulation of heterochromatin would affect mammalian development, we generated transgenic mice that over-express the SUV39H1 HMTase early during embryogenesis. SUV39H1 transgenic mice are growth retarded, display a weak penetrance of skeletal transformations and are largely characterized by impaired erythroid differentiation, consistent with highest transgene expression in foetal liver. Ex vivo transgenic foetal liver cultures initially contain reduced numbers of cells in G1 but progress to immortalized erythroblasts that are compromised in executing an erythroid differentiation programme. The outgrowing SUV39H1-immortalized erythroblasts can maintain a diploid karyotype despite deregulation of several tumour suppressor proteins and dispersed distribution of the heterochromatin component HP1. Together, these data provide evidence for a role of the SUV39H1 HMTase during the mammalian development and indicate a possible function for higher-order chromatin in contributing to the balance between proliferation and differentiation potentials of progenitor cells.
Mech Dev 2001 Sep
PMID:Over-expression of the SUV39H1 histone methyltransferase induces altered proliferation and differentiation in transgenic mice. 1152 Jun 70

Hepatocellular carcinoma (HCC) is one of the most frequent-occurring malignant tumours worldwide, but molecular changes of tumour DNA, with the exception of viral integrations and p53 mutations, are poorly understood. In order to search for common macro-imbalances of genomic tumour DNA, 21 HCCs and 3 HCC-cell lines were characterized by comparative genomic hybridization (CGH), subsequent database analyses and in selected cases by fluorescence in situ hybridization (FISH). Chromosomal subregions of 1q, 8q, 17q and 20q showed frequent gains of genomic material, while losses were most prevalent in subregions of 4q, 6q, 13q and 16q. Deleted regions encompass tumour suppressor genes, like RB-1 and the cadherin gene cluster, some of them previously identified as potential target genes in HCC development. Several potential growth- or transformation-promoting genes located in chromosomal subregions showed frequent gains of genomic material. The present study provides a basis for further genomic and expression analyses in HCCs and in addition suggests chromosome 4q to carry a so far unidentified tumour suppressor gene relevant for HCC development.
Br J Cancer 2001 Sep 01
PMID:Frequent genomic imbalances suggest commonly altered tumour genes in human hepatocarcinogenesis. 1153 Dec 55


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