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 immune system of patients with malignant gliomas is profoundly suppressed. The suppression involves both the cellular and humoral immunity and it is mainly attributable to selective depletion and malfunction of helper T cells. Malignant glioma cells express potent immunosuppressive factors such as transforming growth factor-beta(2), inteleukin-10 and prostaglandin E(2). Malignant glioma cells also produce chemoattractants and immunostimulatory cytokines which may activate the immune cells. However, the production of these stimulatory cytokines is not self-destructive to glioma cells because of the immunosuppression. Rather, the tumour cells use them to gain a growth advantage. Indeed the cytokines may act as a growth stimulator of the tumour cells themselves (autocrine mechanism), they may act as angiogenic factors to endothelial cells (paracrine mechanism) or induce the attracted immune cells to secrete angiogenic factors. Some cytokines produced by malignant glioma cells are known to be growth inhibitory to normal astrocytes. Recent studies on tumour suppressor genes suggest a close link between the aberrant genes and the immunobiologic features of malignant glioma cells.
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PMID:Immunobiology of malignant gliomas. 1863 50

Glioma tumour-suppressor candidate region gene 2 (GLTSCR2/PICT-1) is localized within the well-known 1.4 Mb tumour-suppressive region of chromosome 19q, which is frequently altered in various human tumours, including diffuse gliomas. Aside from its chromosomal localization, several lines of evidence, including PTEN-phosphorylating and cell-killing activities, suggests that GLTSCR2 participates in the suppression of tumour growth and development. However, little is known about the biological functions and molecular mechanisms of GLTSCR2 as a tumour suppressor gene. We investigated the pathological significance of GLTSCR2 expression in association with the development and progression of glioblastomas, the most common malignant brain tumour. We used real-time PCR and western blot analysis to examine the expression levels of GLTSCR2 mRNA and protein in glioblastomas, normal brain tissue and in non-glial tumour tissue of different origin, and found that GLTSCR2 expression is down-regulated in glioblastomas. In addition, direct sequencing analysis and fluorescence in situ hybridization clearly demonstrates the presence of genetic alterations, such as a nonsense mutation and deletion, in the GLTSCR2 gene in glioblastomas. Finally, our immunohistochemical study demonstrates that GLTSCR2 is sequentially down-regulated according to the histological malignant progression of the astrocytic glial tumour. Taken together, our results suggest that GLTSCR2 is involved in astrocytic glioma progression.
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PMID:Suppression of putative tumour suppressor gene GLTSCR2 expression in human glioblastomas. 1872 76

Programmed cell death 4 (PDCD4) is a newly described tumour suppressor that inhibits oncogenesis by suppressing gene transcription and translation. Loss of PDCD4 expression has been found in several types of human cancers including the most common cancer of the brain, the gliomas. However, the molecular mechanisms responsible for PDCD4 gene silencing in tumour cells remain unclear. Here we report the identification of 5'CpG island methylation as the predominant cause of PDCD4 mRNA silencing in gliomas. The methylation of the PDCD4 5'CpG island was found in 47% (14/30) of glioma tissues, which was significantly associated with the loss of PDCD4 mRNA expression (gamma=-1.000, P < 0.0001). Blocking methylation in glioma cells using a DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, restored the PDCD4 gene expression, inhibited their proliferation and reduced their colony formation capacity. Longitudinal studies of a cohort of 84 patients with gliomas revealed that poor prognosis of patients with high-grade tumours were significantly associated with loss of PDCD4 expression. Thus, our current study suggests, for the first time, that PDCD4 5'CpG island methylation blocks PDCD4 expression at mRNA levels in gliomas. These results also indicate that PDCD4 reactivation might be an effective new strategy for the treatment of gliomas.
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PMID:PDCD4 gene silencing in gliomas is associated with 5'CpG island methylation and unfavourable prognosis. 1879 49

Glioblastoma (GBM) is a highly lethal brain tumour presenting as one of two subtypes with distinct clinical histories and molecular profiles. The primary GBM subtype presents acutely as a high-grade disease that typically harbours mutations in EGFR, PTEN and INK4A/ARF (also known as CDKN2A), and the secondary GBM subtype evolves from the slow progression of a low-grade disease that classically possesses PDGF and TP53 events. Here we show that concomitant central nervous system (CNS)-specific deletion of p53 and Pten in the mouse CNS generates a penetrant acute-onset high-grade malignant glioma phenotype with notable clinical, pathological and molecular resemblance to primary GBM in humans. This genetic observation prompted TP53 and PTEN mutational analysis in human primary GBM, demonstrating unexpectedly frequent inactivating mutations of TP53 as well as the expected PTEN mutations. Integrated transcriptomic profiling, in silico promoter analysis and functional studies of murine neural stem cells (NSCs) established that dual, but not singular, inactivation of p53 and Pten promotes an undifferentiated state with high renewal potential and drives increased Myc protein levels and its associated signature. Functional studies validated increased Myc activity as a potent contributor to the impaired differentiation and enhanced renewal of NSCs doubly null for p53 and Pten (p53(-/-) Pten(-/-)) as well as tumour neurospheres (TNSs) derived from this model. Myc also serves to maintain robust tumorigenic potential of p53(-/-) Pten(-/-) TNSs. These murine modelling studies, together with confirmatory transcriptomic/promoter studies in human primary GBM, validate a pathogenetic role of a common tumour suppressor mutation profile in human primary GBM and establish Myc as an important target for cooperative actions of p53 and Pten in the regulation of normal and malignant stem/progenitor cell differentiation, self-renewal and tumorigenic potential.
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PMID:p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. 1894 56

The p53 tumour suppressor protein has long been recognized as the central factor protecting humans from cancer. In this study we evaluated the associations of p53 status and vessel density (angiogenesis) in a set of diffuse low-grade astrocytomas. Immunohistochemistry was performed on 23 diffuse low-grade astrocytomas for CD31 and p53. Mutations in the TP53 gene were identified by PCR amplification of genomic DNA extracted from the indicated tumour tissues. Microvessel counts were done by computer analyses. Intratumoural or peritumoural microvascular hot spots were assessed and analysed from an image taken with a 200x fold magnification. Statistical analysis was performed with Pearson correlation coefficient and Student's t-test. We found that 9/23 (39%) of the astrocytomas stained positive for p53 in the immunohistochemistry. We identified TP53 mutations in 11/23 (47%) of the astrocytomas. No association between micro vessel density (MVD) and p53 immunohistochemical status was found. However, the MVD was significantly increased in p53 mutated low-grade astrocytomas. Furthermore, the absolute vessel number was significantly higher in p53 mutated than in p53 wild-type low-grade astrocytomas. To analyse the molecular background for that epiphenomenon LN229 glioma cells which harbour a TP53 mutation were transfected with a plasmid encoding p53 wild-type and an angiogenesis protein array was performed. We detected a significant increase for thrombospondin-1, coagulation factor III and serpin E1 and a significant decrease of MMP-9 in wild-type p53 transfected LN229 cells. The higher microvessel density and the increased absolute vessel number in p53 mutated tumours supports the importance of p53 for tumour angiogenesis in diffuse low-grade astrocytomas. Our results support the hypothesis that p53 regulates angiogenesis in low-grade astrocytomas.
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PMID:p53-mediated inhibition of angiogenesis in diffuse low-grade astrocytomas. 1942 89

The retinoblastoma gene (RB) is a tumour suppressor gene, of which mutations are associated with carcinogenesis in a broad spectrum of human malignacies. To evaluate its putative role in tumorigenesis in intracranial tumours, we investigated cell lines derived from human gliomas and 91 fresh surgical specimens derived from a broad spectrum of intracranial tumours. We found 7 out of 24 cell lines with markedly reduced levels of the retinoblastoma gene protein (pRB) by Western blot and its mRNA by Northern blot analysis. Such a decrease of RB expression appeared not to be clonal, as none of these lines showed subpopulations with nuclear staining in immunocytochemistry. Loss or decreased expression of pRB, however, could only be detected in a small proportion of the glioma tissues. None of the informative lines or the 21 glioma specimens presented any mutation by Southern blot. Furthermore only in 2 out of 28 pituitary adenomas pRB was undetectable, which is interesting, as heterozygous RB-knockout mice are known to develop pituitary tumours. We conclude that alterations of the RB gene seem to be relevant in only a small subset of gliomas. Our findings also suggest, that not only loss, but also ineffectively low levels of pRB, which are not necessarily caused by mutations might play a role in the pathophysiology of tumours.
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PMID:Expression of retinoblastoma gene in human intracranial neoplasms. 2156 97

A hallmark of cancer is the paradoxical co-presence, in the same tumour, of local and global DNA hypomethylation together with the regional hypermethylation of certain genes. Due to the oncogenic role of these different DNA methylation alterations, two therapeutic strategies are possible: the use of DNA methylating agents (DMA, such as folate) to inhibit global or local DNA hypomethylation or the use of DNA hypomethylating agents (DHA, such as 5-aza-2-deoxycytidine) to abrogate the accumulation of hypermethylated genes. Here we explored the use of folate to treat gliomas in a mouse model, using tumours induced by either PDGF-B or Ras/Akt overexpression, or by ethylnitrosourea (ENU) treatment. Under all conditions the volume of tumours were significantly less in folate treated mice than in untreated mice. Quantitative methylated DNA immunoprecipitation (qMeDIP) and quantitative methylated specific PCR (qMSP) analysis of methylation status showed that folate treatment, increased the methylation level of DNA repeat elements in tumour and in colorectal tissue and that of MGMT and specific oncogenes (PDGF-B or survivin) in tumours (but not in colorectal tissue), but had no effect on the expression of tumour suppressor genes (p53, PTENorbax) in tumours or in colorectal tissue. This suggests that folate has anti-neoplastic effects in gliomas and that no preneoplastic or neoplastic alterations were observed in unaffected colorectal tissue in response to the potential tumourigenic effects of folate. Collectively, our data support the proposal to include folate as a promising adjuvant in the design of anti-glioma therapeutic protocols in clinical studies.
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PMID:Folate supplementation limits the tumourigenesis in rodent models of gliomagenesis. 2232 70

MicroRNAs are strongly implicated in cancer but their specific roles and functions in the major cancers have yet to be fully elucidated. In this study, we defined the expression and function of miR-137, which we found to be downregulated in glioma samples and glioma cells by qRT-PCR. Ectopic expression of miR-137 in glioma cell lines inhibited proliferation and invasion. Using computational and expression analysis, Cox-2 was identified as a candidate target of miR-137. Reporter assay with 3'UTR of Cox-2 cloned downstream of the luciferase gene showed reduced luciferase activity in the presence of miR-137, providing strong evidence that miR-137 was a direct regulator of Cox-2. Expression analysis further revealed that Cox-2 was elevated in glioma and associated with survival of patients. Furthermore, we observed that Cox-2 knockdown resulted in effects similar to those with miR-137 transfection in glioma cells. In conclusion, our study demonstrates that miR-137 deregulation is common in glioma, and restoration of its function inhibits cell proliferation and invasion, suggesting that miR-137 may act as a tumour suppressor.
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PMID:miR-137 is frequently down-regulated in glioblastoma and is a negative regulator of Cox-2. 2240 49

In a strategy to identify novel genes involved in glioma pathogenesis by molecular characterization of chromosomal translocation breakpoints, we identified the KIAA1797 gene, encoding a protein with an as yet undefined function, to be disrupted by a 7;9 translocation in a primary glioblastoma culture. Array-based comparative genomic hybridization detected deletions involving KIAA1797 in around half of glioblastoma cell lines and glioblastomas investigated. Quantification of messenger RNA levels in human tissues demonstrated highest KIAA1797 expression in brain, reduced levels in all glioblastoma cell lines and most glioblastomas and similar levels in glial and neuronal cells by analysis of different hippocampal regions from murine brain. Antibodies against KIAA1797 were generated and showed similar protein levels in cortex and subcortical white matter of human brain, while levels were significantly reduced in glioblastomas with KIAA1797 deletion. By immunofluorescence of astrocytoma cells, KIAA1797 co-localized with vinculin in focal adhesions. Physical interaction between KIAA1797 and vinculin was demonstrated via co-immunoprecipitation. Functional in vitro assays demonstrated a significant decrease in colony formation, migration and invasion capacity of LN18 and U87MG glioma cells carrying a homozygous KIAA1797 deletion ectopically expressing KIAA1797 compared with mock-transduced cells. In an in vivo orthotopic xenograft mouse model, U87MG tumour lesions expressing KIAA1797 had a significantly reduced volume compared to tumours not expressing KIAA1797. In summary, the frequently deleted KIAA1797 gene encodes a novel focal adhesion complex protein with tumour suppressor function in gliomas, which we name 'focadhesin'. Since KIAA1797 genetic variation has been implicated in Alzheimer's disease, our data are also relevant for neurodegeneration.
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PMID:KIAA1797/FOCAD encodes a novel focal adhesion protein with tumour suppressor function in gliomas. 2242 31

Neoplastic transformation appears to be a multi-step process in which the normal controls of cell proliferation and cell-cell interaction are lost, thus transforming normal cells into cancer. The tumorigenic process involves the interplay between oncogenes and tumour suppressor genes. In this study, we have selected the ras family, c-myc and epidermal growth factor receptor (EGFR) genes to detect whether their abnormalities are associated with the expression and progression of glioma cases in Malay patients. We have used the polymerase chain reaction-single stranded conformation polymorphism followed by direct sequencing for the study. For the ras gene family, we screened the point mutations in codons 12 and 61 of the H-, K-, and N-ras gene; for EGFR and c-myc, we analyzed only the exon 1 in glioma samples. In mutational screening analyses of the ras family, c-myc and EGFR gene, there was no mobility shift observed in any tumour analyzed. All patterns of single stranded conformation polymorphism (SSCP) band observed in tumour samples were normal compared to those in normal samples. The DNA sequencing results in all high-grade tumours showed that all base sequences were normal. All 48 patients survived after five years of treatment. In simple logistic regression analysis, variables which were found to be significant were hemiplegia (p=0.047) and response radiotherapy (p=0.003). Hemiplegics were 25 times more likely to have high pathological grade compared to those without. Patients with vascular involvement were 5.5 times more likely to have higher pathological grade. However, these findings were not significant in multivariate analysis. Patients who had radiotherapy were nearly 14 times more likely to have higher pathological grade. Multivariate analysis revealed that patients with hemiplegia were more likely to have higher pathological grade (p= 0.008). Those with higher pathological grading were 80 times more likely to have radiotherapy (p=0.004).
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PMID:Absence of Ras, c-myc and Epidermal Growth Factor Receptor (EGFR) Mutations in Human Gliomas and its Clinical Factors Associated with Pathological Grading After Six Years of Diagnosis in North East Malaysian Patients. 2260 55


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