Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 3p21.3 tumour suppressor gene (TSG) RASSF1A is inactivated predominantly by promoter methylation and rarely by somatic mutations. Recently we demonstrated that epigenetic inactivation of RASSF1A is frequent in both clear cell and papillary adult renal cell carcinomas (even though 3p21.3 allele loss is rare in papillary tumours). Wilms' tumour is the most common childhood kidney tumour, but relatively little is known about its molecular pathogenesis. Thus TSGs such as WT1, p16(CDKN2a) and p53 are inactivated in only a minority of cases. In view of the involvement of RASSF1A in adult renal cancers we investigated RASSF1A as a candidate Wilms' TSG. We detected RASSF1A hypermethylation in 21 of 39 (54%) primary Wilms' tumours. 3p21.3 allele loss was not detected in nine informative Wilms' tumours (five with RASSF1A methylation). In contrast to RASSF1A, only a minority (10.3%) of Wilms' tumours demonstrated p16 promoter methylation. As chromosome 3p allele loss is frequent in colorectal cancer, we proceeded to investigate RASSF1A promoter methylation in colorectal cancer and detected RASSF1A methylation in 80% (4/5) colorectal cancer cell lines and 45% (13/29) primary colorectal cancers. There was no correlation between RASSF1A and p16 methylation in colorectal cancer. We have demonstrated that RASSF1A inactivation is the most frequent genetic or epigenetic event yet reported in Wilms' tumourigenesis and that allelotyping studies may fail to identify regions containing important TSGs.
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PMID:Frequent RASSF1A tumour suppressor gene promoter methylation in Wilms' tumour and colorectal cancer. 1237 Aug 19

Microsatellite instability has been reported in a wide variety of cancer types. Inactivation or loss of tumour suppressor genes has been shown to result in cell cycle deregulation and neoplastic growth. We conducted a microsatellite study using fluorescent-based DNA technology to determine whether mutations in the microsatellite sequences of the deleted in colorectal cancer (DCC) gene, a tumour suppressor at 18q21.1, have any pathologic correlation or prognostic significance in nephroblastomas. Normal and tumour DNA was isolated from 106 cases of nephroblastoma using the standard proteinase K digestion and phenol-chloroform extraction method from paraffin wax-embedded tissue. Polymerase chain reaction using three microsatellite markers; D18S21, D18S34 and D18S58, for the DCC gene were performed. The polymerase chain reaction products were analysed on the ALF Express Automated DNA sequencer. The results were correlated with age at diagnosis, preoperative chemotherapy, clinicopathological stage, histological classification and patient outcome using chi(2) test. Allelic imbalance/loss of heterozygosity appeared to be a more frequent genetic aberration than microsatellite instability with 20% of cases showing allelic imbalance/loss of heterozygosity and only 9% of cases showing microsatellite instability. Genetic aberrations were more frequent in unfavourable histology tumours compared to favourable histology tumours (P=0.012). All patients with genetic aberrations for more than one DCC marker died independent of histological classification and stage (P=0.016). There was no statistically significant difference when DCC aberrations were compared with age at diagnosis, preoperative chemotherapy and clinicopathological stage. In conclusion, this study has found that multiple aberrations involving the DCC locus may play a role in the progression of nephroblastomas, and hence confer a poorer prognosis.
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PMID:Microsatellite analysis of the DCC gene in nephroblastomas: pathologic correlations and prognostic implications. 1463 65

Wt1 is a tumour suppressor gene, mutation of which is a cause of Wilms' tumour, a childhood renal nephroblastoma. Wt1 is expressed in a rich pattern during renal development suggesting that it acts at three stages: determination of the kidney area, the differentiation of nephrons and maturation of glomeruli. Wt1-/- mice confirm that Wt1 is essential for the inception of kidney development; cells that ought to form kidneys die by apoptosis instead. Specific human WT1 mutations cause defects of glomerular maturation (Denys-Drash and Frasier syndromes), providing circumstantial evidence for action of Wt1 during glomerular maturation. There is, however, no genetic evidence for a function during nephron differentiation because this stage is never reached in Wt1-/- mice. We have therefore developed a novel technique, based on small interfering RNA (siRNA), to repress the expression of Wt1 and other specific genes at different stages of kidney development in culture. We find that early repression of Wt1 phenocopies the Wt1-/- mouse, but later repression prevents cells differentiating into nephrons and causes them instead to proliferate abnormally, possibly mimicking aspects of Wilms' tumour. In line with established hypotheses about genetic pathways that control kidney development, we find that repressing Pax2 using siRNAs represses Wt1 expression and blocks both bud growth and nephron differentiation, but that repressing Wnt4 blocks nephron differentiation without affecting Wt1 expression. As well as illuminating previously inaccessible aspects of Wt1 biology, our results suggest that siRNA in organ culture will be a powerful method for analyzing other developmental pathways and testing the effects of stage-specific loss of tumour suppressor genes.
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PMID:Development of an siRNA-based method for repressing specific genes in renal organ culture and its use to show that the Wt1 tumour suppressor is required for nephron differentiation. 1464 1

The 3p21.3 RASSF1A tumour suppressor gene (TSG) provides a paradigm for TSGs inactivated by promoter methylation rather than somatic mutations. Recently, we identified frequent promoter methylation without somatic mutations of SLIT2 in lung and breast cancers, suggesting similarities between SLIT2 and RASSF1A TSGs. Epigenetic inactivation of RASSF1A was first described in lung and breast cancers and subsequently in a wide range of human cancers including neuroblastoma, Wilms' tumour and renal cell carcinoma (RCC). These findings prompted us to investigate SLIT2 methylation in these three human cancers. We analysed 49 neuroblastomas (NBs), 37 Wilms' tumours and 48 RCC, and detected SLIT2 promoter methylation in 29% of NB, 38% of Wilms' tumours and 25% of RCC. Previously, we had demonstrated frequent RASSF1A methylation in the same tumour series and frequent CASP8 methylation in the NB and Wilms' tumour samples. However, there was no significant association between SLIT2 promoter methylation and RASSF1A or CASP8 methylation in NB and RCC. In Wilms' tumour, there was a trend for a negative association between RASSF1A and SLIT2 methylation, although this did not reach statistical significance. No associations were detected between SLIT2 promoter methylation and specific clinicopathological features in the tumours analysed. These findings implicate SLIT2 promoter methylation in the pathogenesis of both paediatric and adult cancers and suggest that further investigations of SLIT2 in other tumour types should be pursued. However, epigenetic inactivation of SLIT2 is less frequent than RASSF1A in the tumour types analysed.
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PMID:SLIT2 promoter methylation analysis in neuroblastoma, Wilms' tumour and renal cell carcinoma. 1473 2

The Wilms' tumour suppressor gene, WT1, encodes a zinc-finger protein that is mutated in Wilms' tumours and other malignancies. WT1 is one of the earliest genes expressed during kidney development. WT1 proteins can activate and repress putative target genes in vitro, although the in vivo relevance of such target genes often remains unverified. To better understand the role of WT1 in tumorigenesis and kidney development, we need to identify downstream target genes. In this study, we have expression profiled human embryonic kidney 293 cells stably transfected to allow inducible WT1 expression and mouse mesonephric M15 cells transfected with a WT1 antisense construct to abolish endogenous expression of all WT1 isoforms to identify WT1-responsive genes. The complementary overlap between the two cell lines revealed a pronounced repression of genes involved in cholesterol biosynthesis by WT1. This pathway is transcriptionally regulated by the sterol responsive element-binding proteins (SREBPs). Here, we provide evidence that the C-terminal end of the WT1 protein can directly interact with SREBP, suggesting that WT1 may modify the transcriptional function of SREBPs via a direct protein-protein interaction. Therefore, the tumour suppressor activities of WT1 may be achieved by repressing the mevalonate pathway, thereby controlling cellular proliferation and promoting terminal differentiation.
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PMID:Anlaysis of complementary expression profiles following WT1 induction versus repression reveals the cholesterol/fatty acid synthetic pathways as a possible major target of WT1. 1502 18

Wilms' tumour is a paediatric malignancy of the kidneys and is the most common solid tumour found in children. The Wilms' tumour suppressor protein WT1 is mutated in approximately 15% of Wilms' tumours, and is aberrantly expressed in many others. WT1 can manifest both tumour suppressor and oncogenic activities, but the reasons for this are not yet clear. The Wilms' tumour suppressor protein WT1 is a transcriptional activator, the function of which is under cell-context-specific control. We have previously described a small region at the N-terminus of WT1 (suppression domain) that inhibits the transcriptional activation domain by contacting a co-suppressor protein. We recently identified BASP1 as one of the components of the co-suppressor. Here, we analyse the mechanism of action of the WT1 suppression domain, and discuss its function in the context of the role of WT1 as a regulator of development.
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PMID:Transcriptional regulation by the Wilms' tumour suppressor protein WT1. 1550 28

Constitutional chromosome deletions can predispose to the development of cancer with the phenotypic characteristics of inherited cancer syndromes, when the deleted region encompasses a tumour suppressor gene. Examples of such conditions are represented by the cytogenetic deletions associated with retinoblastoma, Wilms tumour and familial adenomatous polyposis. So far, no constitutional deletions involving the genes implicated in hereditary non-polyposis colorectal cancer (HNPCC) have been identified. This may be at least partially because of the lack of distinctive phenotypic manifestations in HNPCC. We describe the first case of a constitutional microdeletion associated with HNPCC. Suspicion of a microdeletion was prompted by the association of mental retardation, postnatal growth deficiency, minor congenital anomalies and early onset (37 years) sporadic colon cancer. The patient was found to harbour a microdeletion within chromosome 2p16-p21, including the MSH2 gene. Since there are very few reports of deletions of the 2p16-p21 region, our observation sets the grounds for the definition of a novel multiple congenital anomaly/mental retardation/cancer microdeletion syndrome.
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PMID:A novel microdeletion syndrome with loss of the MSH2 locus and hereditary non-polyposis colorectal cancer. 1567 31

Wilms' tumour, or nephroblastoma, is a common childhood tumour that is intimately linked to early kidney development and is often associated with persistent embryonic renal tissue and other kidney abnormalities. WT1, the first gene found to be inactivated in Wilms' tumour, encodes a transcription factor that functions as both a tumour suppressor and a critical regulator of renal organogenesis. Our understanding of the roles of WT1 in tumour formation and organogenesis have advanced in parallel, providing a striking example of the intersection between tumour biology, cellular differentiation and normal organogenesis.
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PMID:Wilms' tumour: connecting tumorigenesis and organ development in the kidney. 1611 Mar 18

Using arbitrary primed-PCR (AP-PCR), we have identified a novel genetic alteration located at chromosome 11q23.2 and this genetic alteration was common in 38% of the human Wilms tumour samples analysed. Further characterisation by cloning and sequencing of this genomic region revealed that it represents a part of an uncharacterised gene. We have named this gene as Sporadic Kidney Cancer Gene-1 (SKCG-1). Using fluorescence in situ hybridisation (FISH) approach, we established its localisation on the chromosome 11q23.2. Northern analysis revealed the transcript size of SKCG-1 of 2.09 kb and this was further confirmed by full-length cDNA sequence. Sequence analysis revealed an active translation start site (ATG sequence), a polyadenylation signal sequence (AATAAA), and an open reading frame (ORF) encoding a peptide of 124 amino acids in the cDNA sequence of SKCG-1. Analysis of genomic sequence of SKCG-1 revealed a promoter region containing TATA box located at -13 bp upstream of transcription start site. The AP-PCR, SCAR, and Southern blot analyses indicated genomic loss of SKCG-1 in Wilms tumours. The transcript of SKCG-1 was abundantly present in brain, kidney, liver, testis, salivary gland, foetal brain, foetal liver, whereas relatively lower expression in heart, stomach, prostate and no expression in spleen, colon, lung, small intestine, muscle, adrenal gland, uterus, skin, PBL, and bone marrow was detected. The expression of this gene transcript was either very less or undetectable in Wilms and breast tumours compared to their matched uninvolved tissues. Inhibition of SKCG-1 by siRNA resulted in increased cell proliferation of kidney epithelial cells. Based on the presence of two transmembrane regions in its peptide, SKCG-1 has been predicted as a transmembrane protein. Thus, the findings of this study revealed (i) SKCG-1, a new gene located at 11q23.2 and harbouring genetic alteration in Wilms tumours, (ii) the presence of SKCG-1 gene transcripts in various human normal tissues and its lower expression or absence in Wilms and breast tumours indicate that it may be associated with tumour growth suppressor activity, (iii) the presence of an open reading frame in the cDNA sequence of SKCG-1 indicates that it has potential to encode a protein, (iv) increased cell growth by silencing this gene in HEK293 cells further supports a potential role of this gene in growth of kidney epithelial cells. Our findings suggest that SKCG-1 may have a tumour suppressor role, and implicate genetic alteration in this gene as a potential oncogenic pathway and therapeutic target in kidney and breast cancer.
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PMID:SKCG-1: a new candidate growth regulatory gene at chromosome 11q23.2 in human sporadic Wilms tumours. 1662 58

Taurine transport undergoes an adaptive response to changes in taurine availability. Unlike most amino acids, taurine is not metabolized or incorporated into protein but remains free in the intracellular water. Most amino acids are reabsorbed at rates of 98-99%, but reabsorption of taurine may range from 40% to 99.5%. Factors that influence taurine accumulation include ionic environment, electrochemical charge, and post-translational and transcriptional factors. Among these are protein kinase C (PKC) activation and transactivation or repression by proto-oncogenes such as WT1, c-Jun, c-Myb and p53. Renal adaptive regulation of the taurine transporter (TauT) was studied in vivo and in vitro. Site-directed mutagenesis and the oocyte expression system were used to study post-translational regulation of the TauT by PKC. Reporter genes and Northern and Western blots were used to study transcriptional regulation of the taurine transporter gene (TauT). We demonstrated that (i) the body pool of taurine is controlled through renal adaptive regulation of TauT in response to taurine availability; (ii) ionic environment, electrochemical charge, pH, and developmental ontogeny influence renal taurine accumulation; (iii) the fourth segment of TauT is involved in the gating of taurine across the cell membrane, which is controlled by PKC phosphorylation of serine 322 at the post-translational level; (iv) expression of TauT is repressed by the p53 tumour suppressor gene and is transactivated by proto-oncogenes such as WT1, c-Jun, and c-Myb; and (v) over-expression of TauT protects renal cells from cisplatin-induced nephrotoxicity.
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PMID:The taurine transporter: mechanisms of regulation. 1673 43


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