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)

Using restriction fragment length polymorphism (RFLP) analysis, we demonstrated in 4 of 20 patients with astrocytomas loss of heterozygosity on the short arm of chromosome 17 (17p), in the telomeric segment distal to DNA marker pEW301 (locus D17S58). The loss of heterozygosity may uncover a mutation in a tumour suppressor gene and thus lead to or permit tumour formation. The p53 tumour suppressor gene, which is localized at 17p13, is a likely candidate for the tumour suppressor gene involved. Of the 4 patients with loss of heterozygosity on 17p, one patient had a grade I astrocytoma, another patient had a grade II astrocytoma and 2 patients had glioblastoma multiforme. Since the loss of heterozygosity on 17p was detected in low-grade as well as in high-grade astrocytomas, it is possible that p53 suppressor gene loss may be an early genetic event in the multistep process of astrocytoma formation.
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PMID:Loss of heterozygosity on the short arm of chromosome 17 in human astrocytomas. 135 Dec 57

The earliest genetic alteration in human astrocytoma progression is mutation of the p53 tumour suppressor gene, while one of the earliest phenotypic changes is the stimulation of neovascularization. Here, we tested the role of p53 in the angiogenic process by introducing a tetracycline-regulated wild type p53 gene into null glioblastoma cells. The parental cells expressed strong angiogenic activity while upon induction of wild type, but not mutant, p53 expression, the cells secreted a factor able to neutralize the angiogenicity of the factors produced by the parental cells as well as of basic fibroblast growth factor.
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PMID:Release of an inhibitor of angiogenesis upon induction of wild type p53 expression in glioblastoma cells. 753 Oct 56

Among tumours of the nervous system, mutations of the p53 tumour suppressor gene are largely restricted to neoplasms of astrocytic origin. These are the most common human brain tumours and span a wide range of biologic behavior, from the slowly growing low-grade astrocytoma (WHO Grade II) to anaplastic astrocytoma (WHO Grade III) and, ultimately, the glioblastoma multiforme (WHO Grade IV). In low grade astrocytomas, p53 mutations with or without loss of heterozygosity on chromosome 17p are the principle detectable change. Anaplastic astrocytomas contain p53 mutations in approximately one third of cases and further display loss of heterozygosity on chromosome 19q and homozygous loss of 9p21, tentatively identified as multiple tumour suppressor 1 (MTS-1). In addition to these genetic alterations, glioblastomas show loss of chromosome 10 and amplification of the EGF receptor gene at an incidence of > 60% and > 40%, respectively. The type and distribution of p53 mutations are not suggestive of specific environmental carcinogens operative in their etiology.
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PMID:Genetic alterations associated with glioma progression. 753 15

The treatment and prognosis of patients with cerebral astrocytic tumours are currently guided by histopathological classification. This study evaluates immunohistochemistry using Ki-67, an antibody to a nuclear protein expressed in proliferating cells, and DO-7, an antibody to the product of the tumour suppressor gene p53, as prognostic indicators for these tumours. Immunohistochemistry with Ki-67 has been correlated with the behaviour of many different tumours, but its value as a prognostic indicator in astrocytic tumours is diminished by the conflicting results of previous studies. Immunohistochemistry with antibodies to the p53 protein has been used as a prognostic indicator in melanomas and some carcinomas, but the relation between prognosis and accumulation of this protein in astrocytic tumours has not been clarified. We have tested the hypothesis that survival is correlated with Ki-67 immunolabelling indices (LIs) and patterns of p53 immunolabelling in the cerebral astrocytic tumours of a large cohort of patients (n = 123) for whom clinical indices were well documented. Astrocytic tumours were divided into three histological types: fibrillary astrocytoma (n = 24), anaplastic astrocytoma (n = 31), and glioblastoma (n = 68). Histological type and patient age were independent predictors of survival. Median Ki-67 LIs differed significantly (P < 0.0001) between the types of astrocytic tumour, and tumours with a Ki-67 LI < 2% had a significantly (P < 0.0001) better prognosis. Ki-67 LI as a continuous variable carried a significant (P = 0.0043) unadjusted hazard to survival which was lost when adjusted for other variables, notably histological type. By contrast, no relation was found between survival and three categories of p53 labeling (p53-negative, p53 LI < 40%, and p53 LI > 60%). The results indicate that, whereas Ki-67 immunohistochemistry predicts survival in patients with astrocytic tumours, conventional histological appraisal remains the best guide to prognosis, and immunohistochemistry for p53 has no value in the assessment of these tumours.
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PMID:Prognostic indicators in a range of astrocytic tumours: an immunohistochemical study with Ki-67 and p53 antibodies. 756 22

A human pilocytic astrocytoma-derived cell line, a grade III astrocytoma-derived cell line, and a glioblastoma-derived cell line were transfected with the human wild-type p53 gene, in order to demonstrate the possible suppressor role of this gene in low grade as well as in high grade human astrocytomas. p53 exhibited a strong growth suppressor effect on the three cell lines studied, irrespective of the grade of malignancy of the tumours from which they originate. Furthermore, the p53 gene elicited important morphological changes in these cell lines. p53-Transfected cells displayed a flat morphology, a large cell body, and a stellate shape with long processes, characteristic of differentiated astrocytes. In addition, the growth inhibitory effect of p53 was found not to be due to induction of apoptosis. These results indicate that p53 plays a tumour suppressor role in low grade and high grade human astrocytomas and raise the possibility of the involvement of p53 in glioma cell differentiation in vitro.
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PMID:Human wild type p53 inhibits cell proliferation and elicits dramatic morphological changes in human glioma cell lines in vitro. 770 71

We analysed for loss of alleles on chromosome 10, 25 astrocytomas, 3 ependymomas, 2 medulloblastomas, 2 juvenile pilocytic astrocytomas, 2 gangliogliomas, 1 subependymal giant cell astrocytoma and 1 anaplastic oligoastrocytoma. A battery of 12 DNA markers spanning chromosome 10 was employed. Loss of heterozygosity on chromosome 10 was seen in 16 tumours (13 glioblastoma multiforme, 2 anaplastic astrocytomas, and 1 anaplastic oligoastrocytoma), but not in any of the low-grade astrocytomas examined. High-resolution restriction fragment length polymorphism (RFLP) analysis showed that the loss of alleles in a number of tumours involved two separate large regions of chromosome 10 (10p-proximal 10q and distal 10q). However, a small common region of deletion overlap could not be identified. Our data indicate that the loss of alleles on chromosome 10 is a common finding, seen in over two-thirds of malignant astrocytomas, and may be suggestive of the presence of two or more chromosome 10 tumour suppressor genes involved in astrocytoma formation. Nevertheless, the possibility of these genetic changes being secondary and not causative of the deregulated cell growth cannot be excluded. Regardless of the mechanisms involved, however, chromosome 10 deletions may be a genetic marker for malignant astrocytomas.
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PMID:Loss of heterozygosity for alleles on chromosome 10 in human brain tumours. 809 56

Tuberous sclerosis (TSC) is an autosomal dominant condition with characteristic skin lesions, mental handicap, seizures and the development of hamartomas in the brain, heart, kidneys and other organs. Linkage studies have shown locus heterogeneity with a TSC gene mapped to chromosome 9q34 and a second, recently identified on 16p13.3. We have analysed DNA markers in eight hamartomas and one tumour from TSC patients and found allele loss on 16p13.3 in three angiomyolipomas, one cardiac rhabdomyoma, one cortical tuber and one giant cell astrocytoma. We suggest that the TSC gene on 16p13.3 functions like a tumour suppressor gene, in accordance with Knudsen's hypothesis.
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PMID:Loss of heterozygosity on chromosome 16p13.3 in hamartomas from tuberous sclerosis patients. 816 74

Neoplastic transformation occurs in all glial cell types of the human nervous system, producing a wide variety of clinico-pathological entities and morphological variants. Astrocytomas are most common and span an unusually wide spectrum, ranging from the slowly growing juvenile pilocytic astrocytoma to the highly malignant glioblastoma multiforme. Diffusely infiltrating astrocytomas of the cerebral hemispheres show an inherent tendency for progression towards a more malignant phenotype. This change is morphologically categorized in histologic grading schemes (e.g., WHO Grade II to IV) and is associated with the sequential acquisition of genetic alterations, including mutations in the p53 and homozygous deletions of the p16 tumour suppressor genes. Loss of heterozygosity on chromosomes 10 and 19q as well as amplification of the EGF receptor are largely restricted to malignant gliomas and thus considered late events in astrocytoma progression. Gliomas often show phenotypic expression of different glial cell lineages (e.g., oligoastrocytoma). Recent studies suggest that the occurrence of mixed gliomas is not indicative of a polyclonal origin but rather reflects altered gene expression, leading to a change in the balance of growth factors influencing glioma differentiation.
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PMID:Histopathology, classification, and grading of gliomas. 858 58

Amongst the human astrocytic tumours, the commonest of primary brain tumours, the clinical outcome of astrocytoma (AS) is significantly better than anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM). Often, low grade tumours can progress to or recur with a more malignant phenotype. Recent loss of heterozygosity (LOH) reports suspect the involvement of a tumour suppressor gene, different from p53, in the 17p13.3 region of the human chromosome. However, the effect of LOH of 17p13.3 region on tumour histology at presentation and prognosis is as yet undefined. As a first step to define the role of this putative oncogene in astrocytic tumour progression, we correlated the LOH of a locus, D17S379, in 17p13.3 region and the p53 locus in 17p13.1 region with the histopathology of astrocytic tumours by PCR based microsatellite and restriction fragment length polymorphism of DNA extracted from microdissected paraffin sections of 45 astrocytic tumours of different histopathological grades. LOH of D17S379 was significantly associated (P=0.02) with AA and GBM (high grade malignancy), while no such preferential association was found with LOH of p53. There were no mutations in the exons 5 to 9 of p53 gene in the five tumours with LOH of D17S379 but not of p53 region. In a case of AA with a heterogenous microscopic appearance, heterozygosity of D17S379 was lost only in the area with a more malignant histology while both areas had no LOH or mutation of p53. A locus at the 17p13.3 region, independent of the p53 locus, is involved in a large subset of astrocytic tumours during transformation into a more malignant phenotype, and thus may be a link in the chain of genetic events occurring in astrocytic tumour progression.
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PMID:Loss of heterozygosity of a locus on 17p13.3, independent of p53, is associated with higher grades of astrocytic tumours. 926 74

The gemistocytic astrocytoma is a histological variant of diffuse astrocytomas and is characterised by the presence of large, GFAP-expressing neoplastic astrocytes (gemistocytes) and a tendency towards rapid progression to glioblastoma. In this study, we analyzed 28 gemistocytic astrocytomas (mean fraction of gemistocytes, 35.0+/-9.9%) for mutations in the p53 and PTEN (MMAC1) tumour suppressor genes. Single strand conformation polymorphism (SSCP), followed by direct DNA sequencing of p53 exons 5-8, revealed a mutation in 23 of 28 (82%) cases. Regional analysis of four tumours revealed identical p53 mutations in gemistocytic and fibrillary tumour areas. In contrast, none of 15 gemistocytic astrocytomas (WHO Grade II) and only two of 11 (18%) anaplastic gemistocytic astrocytomas (WHO Grade III) contained a PTEN mutation. Of these, one was a 1 bp deletion in codon 345 and the other a 1 bp insertion in intron 4. Differential PCR did not reveal homozygous PTEN deletion in any of the tumours analysed. These results indicate that p53 mutations are a genetic hallmark of gemistocytic astrocytomas, whilst PTEN mutations are absent in low-grade and rare in anaplastic gemistocytic astrocytomas.
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PMID:p53 and PTEN gene mutations in gemistocytic astrocytomas. 965 Jul 46


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