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)

Inactivation of tumour suppressor gene(s) (TSGs) on 3p appears to be a critical event in the pathogenesis of clear cell renal cell carcinoma (CC-RCC). Analysis of loss of heterozygosity (LOH) in sporadic RCC samples has implicated roles for TSGs in three specific regions of 3p in RCC development: (1) 3p12-p14, which includes the breakpoint of the familial t(3;8) constitutional translocation involved in hereditary RCC development and a recently cloned putative TSG, the FHIT gene: (2) 3p21.2-p21.3, a common region of deletion in many cancers including lung; and (3) 3p25-p26, which contains the von Hippel-Lindau (VHL) disease TSG. We and others have shown that most primary sporadic CC-RCCs contain somatic VHL gene mutations, clearly implicating inactivation of the VHL gene in the pathogenesis of CC-RCC. It is not known if CC-RCC without VHL gene mutations have alternative mechanisms of VHL gene inactivation or result from an alternative non-VHL pathway to RCC, e.g., inactivation of TSGs in 3p12-p21. We and others have reported hypermethylation and silencing of the VHL TSG in RCC from patients with VHL disease and in CC-RCC cell lines. However, the incidence and specificity of VHL methylation in primary sporadic RCC has not been defined. Therefore, we analysed methylation of the VHL, CDKN2, MYC, and H19 genes in primary RCC samples. Hypermethylation of the VHL promoter region was detected in 11% (11/99) of the primary RCCs analysed. In 10 of these tumours, there was no evidence of concomitant VHL gene mutation. VHL methylation was specific to CC-RCC (15%, 7/45) but was not detected in any non-CC tumours (n = 16). None of the 11 RCCs methylated at VHL had evidence of methylation at either CDKN2 or MYC (methylation at CDKN2 was, however, detected in 3%, or 1/33, of RCCs without VHL methylation). A normal methylation pattern at H19 was demonstrated in the three RCCs with methylated VHL analysed. Previous studies have suggested that, in addition to VHL, other 3p TSGs at 3p12-p14 and 3p21 may be involved in CC-RCC tumourigenesis. However, the interpretation of these studies has been difficult because information on VHL gene status has not been available for these data sets. Therefore, we investigated a subset of 55 sporadic RCCs (of known VHL gene methylation and mutation status) for LOH at polymorphic markers close to candidate TSG loci in the 3p14.2 and 3p21.2-p21.3 regions. Among tumours with LOH at one or more 3p markers, the incidence of 3p25 allele loss was higher in tumours with VHL alterations (mutation or methylation) than in those without. For tumours without detectable VHL alterations, the frequency of 3p14-p21 LOH was significantly higher than the frequency of 3p25-p26 LOH (93%, 13/14 vs. 43%, 6/14; P = 0.013), whereas, in RCC samples with VHL methylation or mutation, the frequency of 3p14-p21 LOH did not differ from that of sp25-p26 (72%, 18/25 vs. 59%, 13/22; P = 0.376). None of the 11 RCCs with 3p25 allele loss that were informative at 3p21 and 3p14 showed LOH at 3p25 only. These findings suggest that (1) VHL methylation is a specific and important event in the pathogenesis of CC-RCC; (2) in CC-RCC with 3p LOH but without VHL inactivation, mutations in TSGs at 3p14-p21 appear to have a primary role in tumourigenesis; and (3) inactivation of other 3p TSGs in addition to VHL may also be required for malignant transformation in tumours with VHL gene inactivation.
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PMID:Inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene and allelic losses at chromosome arm 3p in primary renal cell carcinoma: evidence for a VHL-independent pathway in clear cell renal tumourigenesis. 962 31

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.
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PMID:The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. 972 36

Undifferentiated nasopharyngeal carcinoma (NPC) is an epithelial malignancy that is consistently associated with Epstein-Barr virus (EBV) but which very rarely has p53 gene mutations in primary tumours. Since the tumour suppressor p53 is mutated in most human cancers or the wild type protein is inactivated in a significant number of the remainder, here we have investigated cellular factors that could compromise p53 function in primary NPC. Twenty-five primary tumours were judged to carry only wild type p53 by SSCP analysis of all exons and sequence determination of exons 4-9. Only one tumour was found to express significant levels of hMdm2 and in 24/25 there were no detectable mutations or deletions in exons 1beta and 2 of the p14(ARF) gene. However, immunohistochemistry consistently revealed that all the tumour cells express substantial amounts of the p53-related protein p63. Semi-quantitative RT-PCR analysis of mRNA from tumour biopsies showed that the dominant species expressed was invariably the truncated deltaN-isotype. Since this can block p53-mediated transactivation, it is potentially a dominant-negative isoform. In normal nasopharyngeal epithelium the distribution of p63 was restricted to the proliferating basal and suprabasal layers. We suggest that deltaN-p63 is a good candidate as a suppressor of wild type p53 function in these tumours and also that it may prove to be a valuable diagnostic marker for undifferentiated NPC.
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PMID:High level expression of deltaN-p63: a mechanism for the inactivation of p53 in undifferentiated nasopharyngeal carcinoma (NPC)? 1091 1

The MDM2 oncoprotein is a negative regulatory partner of the p53 tumour suppressor. MDM2 mediates ubiquitination of p53 and targets the protein to the cytoplasm for 26S proteosome-dependent degradation. In this paper, we show that MDM2 is modified in cultured cells by multisite phosphorylation. Deletion analysis of MDM2 indicated that the sites of modification fall into two clusters which map respectively within the N-terminal region encompassing the p53 binding domain and nuclear export sequence, and the central acidic domain that mediates p14(ARF) binding, p53 ubiquitination and cytoplasmic shuttling. The data are consistent with potential regulation of MDM2 function by multisite phosphorylation.
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PMID:Multiple sites of in vivo phosphorylation in the MDM2 oncoprotein cluster within two important functional domains. 1092 93

The melanoma-astrocytoma syndrome is characterized by a dual predisposition to melanoma and neural system tumours, commonly astrocytoma. Germline deletions of the region on 9p21 containing the CDKN2A and CDKN2B genes and CDKN2A exon 1beta have been reported in kindreds, implicating contiguous tumour suppressor gene deletion as a cause of this syndrome. We describe a family characterized by multiple melanoma and neural cell tumours segregating with a germline deletion of the p14(ARF)-specific exon 1beta of the CDKN2A gene. This deletion does not affect the coding or minimal promoter sequences of either the CDKN2A or CDKN2B genes. Our results are consistent with either: (i) loss of p14(ARF) function being the critical abnormality associated with this syndrome, rather than contiguous loss of both the CDKN2A and CDKN2B genes as suggested previously; or (ii) disruption of expression of p16 by mechanisms as yet unknown.
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PMID:A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family. 1113 14

The unique INK4A/ARF locus at chromosome 9p21 encodes two distinct proteins that intimately link the pRB and p53 tumour suppressor pathways. p16INK4A has been identified as an inhibitor of the cell cycle, capable of inducing arrest in G1 phase. p14/p19ARF on the other hand can induce both G1 and G2 arrest due to its stabilizing effects on the p53 transcription factor. In addition to their roles in growth arrest, both proteins are involved in cellular senescence and apoptosis. The frequent mutation or deletion of INK4A/ARF in human tumours as well as the occurence of tumours in the murine knockout models have identified both p16 and ARF as bona fide tumour suppressors.
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PMID:The INK4A/ARF locus: role in cell cycle control and apoptosis and implications for glioma growth. 1140 94

p53 and p73 proteins activate similar target genes and induce apoptosis and cell cycle arrest. However, p53, but not p73 is considered a tumour-suppressor gene. Unlike p53, p73 deficiency in mice does not lead to a cancer-prone phenotype, and p73 gene is not mutated in human cancers, including hepatocellular carcinoma. Here we report that normal liver cells express only DeltaN-p73 transcript forms giving rise to the synthesis of N-terminally truncated, transcriptionally inactive and dominant negative p73 proteins. In contrast, most hepatocellular carcinoma cells express TA-p73 transcript forms encoding full-length and transcriptionally active p73 proteins, in addition to DeltaN-p73. We also show that together with the acquired expression of TA-p73, the 'retinoblastoma pathway' is inactivated, and E2F1-target genes including cyclin E and p14(ARF) are activated in hepatocellular carcinoma. However, there was no full correlation between 'retinoblastoma pathway' inactivation and TA-p73 expression. Most TA-p73-expressing hepatocellular carcinoma cells have also lost p53 function either by lack of expression or missense mutations. The p73 gene, encoding only DeltaN-p73 protein, may function as a tumour promoter rather than a tumour suppressor in liver tissue. This may be one reason why p73 is not a mutation target in hepatocellular carcinoma.
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PMID:Acquired expression of transcriptionally active p73 in hepatocellular carcinoma cells. 1152 99

The cell cycle inhibitor p15(INK4B) is frequently inactivated by homozygous deletions together with p16(INK4a)/p14(ARF) in many tumour types. Although it is now well established that p16(INK4a) and p14(ARF) act as tumour suppressor genes, the role of p15(INK4b) remains to be well defined. In order to explore the possibility of a selective deregulation of p15(INK4b) in human lung carcinogenesis, we studied p15(INK4b) status in neuroendocrine (NE) lung tumours where homozygous deletions of the p16(INK4a)/p14(ARF) locus are rarely observed. Expressions of p15 and p15.5 protein isoforms were analysed in a series of eight control normal lung, 12 tumour-associated normal lung, five low grade and 15 high grade neuroendocrine (NE) lung tumours and relationship with a specific p15(INK4b) methylation status was studied. Using Western blot analysis, we showed that p15 and p15.5 isoforms displayed a high heterogeneous pattern of expression in both normal and tumour tissues. P15 and p15.5 expressions were correlated in control normal lung (P<0.04) whereas they were not in tumours and associated normal lung. The level of p15.5 was significantly higher in associated normal lung and in tumours (P<0.02 respectively), specially in low grade tumours (P<0.01), than in control normal lung. Furthermore, p15.5 expression was more variable in tumours than in normal lung (P<0.01) and in low grade than in high grade NE lung tumours (P<0.02). Levels of p15 and p15.5 were distinct (up- or downregulated) from those observed in paired normal lung in 4/12 (33%) and 10/12 (83%) tumours respectively. Aberrant methylation at the 5' end of p15(INK4b) gene was observed in 15% of NE lung tumours using PCR-based assay, in a region proximal to the translation start where methylation did not occur in control and associated normal lung. However, no correlation could be assessed with protein status. MSP analysis of CpG islands proximal to the transcription start revealed methylation in all normal and tumour samples. No correlation was found between p15(INK4b) and p16(INK4a) or p14(ARF) status. These data suggest that complex deregulation of p15.5 is implicated in the carcinogenesis of human NE lung tumours independently of p16(INK4a) and p14(ARF) status.
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PMID:Expression of p15 and p15.5 products in neuroendocrine lung tumours: relationship with p15(INK4b) methylation status. 1164 84

The INK4a-ARF (CDKN2A)- locus on chromosome 9p21 encodes for two tumour suppressor proteins, p16(INK4a) and p14(ARF), that act as upstream regulators of the Rb-CDK4 and p53 pathways. To study the contribution of each pathway in tumorigenesis of hepatocellular carcinoma (HCC), we analysed the alterations of p14(ARF), p16(INC4a) and p53. After microdissection, DNA of 71 hepatocellular carcinomas was analysed for INK4-ARF inactivation and p53 mutation by DNA sequence analysis, methylation-specific PCR (MSP), restriction-enzyme related polymerase chain reaction (RE-PCR), mRNA expression and immunohistochemistry. In addition, microdeletion of p14(ARF) and p16(INC4a) were assessed by differential PCR. Inactivation of p14(ARF) was found in 11/71 cases (15%), alterations of p16(INK4a) occurred in 47/71 carcinomas (66%), which correlated with loss of mRNA transcription. Five tumours (7%) had homozygous deletions of the INK4a-ARF locus. We failed to detect specific mutations of both exons. P16(INK4a) methylation with an unmethylated p14(ARF) promotor appeared in 39 cases. Mutations of p53 were found in 30 of 71 HCC (42%), and only one of them harboured p14(ARF) inactivation. We failed to establish alterations of the INK4a-ARF locus or p53 status as independent prognostic factor in these tumours. Our data indicate, that p14(ARF) methylation occurs independently of p16(INK4a) alterations in a subset of HCC together with wild type p53. The INK4a-ARF-/p53-pathway was disrupted in 86% of HCC, either by p53 mutations or by INK4a-ARF inactivation, and may have co-operative effects in hepatocarcinogenesis.
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PMID:INK4a-ARF alterations and p53 mutations in hepatocellular carcinomas. 1170 35

Cancer is an epigenetic disease at the same level that it can be considered a genetic disease. In fact, epigenetic changes, particularly DNA methylation, are susceptible to change and are excellent candidates to explain how certain environmental factors may increase the risk of cancer. The delicate organization of methylation and chromatin states that regulates the normal cellular homeostasis of gene expression patterns becomes unrecognizable in the cancer cell. The genome of the transformed cell undergoes simultaneously a global genomic hypomethylation and a dense hypermethylation of the CpG islands associated with gene regulatory regions. These dramatic changes may lead to chromosomal instability, activation of endogenous parasitic sequences, loss of imprinting, illegitimate expression, aneuploidy, and mutations, and may contribute to the transcriptional silencing of tumour suppressor genes. The hypermethylation-associated inactivation affects virtually all of the pathways in the cellular network, such as DNA repair (hMLH1, BRCA1, MGMT, em leader), the cell cycle (p16(INK4a), p14(ARF), p15(INK4b), ...), and apoptosis (DAPK, APAF-1, ...). The aberrant CpG island methylation can also be used as a biomarker of malignant cells and as a predictor of their behaviour, and may constitute a good target for future therapies.
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PMID:Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumours. 1174 35


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