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Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Few reports are available on mutations in the promoter of tumour suppressor genes like p16, WT1 and Rb in cancers. However, the involvement of p53 promoter in cancers is not clearly known. Further, methylation of CpG sites is a major contributor of mutations in several genes. So an attempt has been made to determine the mutation and methylation status of p53 promoter in breast tumours. Results have demonstrated absence of mutations and deletions in p53 promoter, leading us to conclude that mutation of p53 promoter is probably not a significant factor in breast tumorigenesis. Methylation analysis has shown that the CCGG sites in the p53 promoter are unmethylated unlike that of its exons. Further, it has been shown that there is no change in the methylation profile of the CCGG sites in breast tumours. However, such studies are to be conducted in different types of tumours to define the role of p53 promoter mutation and methylation in the process of tumorigenesis.
Tumour Biol
PMID:Mutation and methylation status of p53 gene promoter in human breast tumours. 1056 80

Gene therapy encompasses deliberate alteration of the genetic material of cancer cells. Somatic-cell therapy involves the administration to cancer patients of living cells that have been genetically manipulated or processed to change their biological characteristics. Gene therapy of cancer, although much hyped, is still in its very early infancy. Current approaches to delivering genes into cells include physico-chemical methods, viral vectors and direct DNA injection. None of these strategies is in any way perfect and their efficacy leaves much to be desired. Based on the somatic mutation theory of carcinogenesis, it would be attractive to repair genetic alterations responsible for neoplastic transformation and clonal evolution of cancer cells. Attempts have been made to replace inactivated tumour suppressor genes in cancer cells through intact wild type gene copies, or to suppress the leukaemogenic effects of chromosomal fusion genes in leukaemia through antisense oligonucleotides. One of the snags of these concepts is that cancer cells harbour several if not myriads of mutated genes, and clonal tumour heterogeneity seems to be the rule rather than the exception. It is at present impossible to repair all gene mutations in cancer lesions of a given patient if such were to be the aim of therapy. Nevertheless, some interesting clinical data have been reported. These include the local injection via bronchoscopy of p53 wild type gene copies into p53-deficient lung cancer lesions and other tumours. Somatic-cell therapy includes a considerable spectrum of interventions. Tumour cells may be transduced with genes which upon their expression will render the tumour cells more immunogenic. Tumour-infiltrating lymphocytes may be harvested, transduced with a gene of interest and re-injected. Since they recognise tumours specifically, they will serve as vehicles to carry therapeutic genes into cancer lesions where the gene product can exert an anti-cancer effect. Such attempts might increase the immunogenicity of tumours considerably. Examples are the transduction of tumour-infiltrating lymphocytes with a gene for tumour necrosis factor alpha or the transduction of tumour cells with the gene for granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with metastatic renal cell carcinoma. Protocols on gene therapy and somatic-cell therapy seem to be a worthy goal of cancer research. However, it seems unlikely that gene therapy will provide magic anti-cancer bullets in the near future or the definitive cancer cure, although this is often promised in the media. Careful clinical and laboratory research will pave the way towards stepwise improvement of cancer patient care.
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PMID:[Molecular therapy in malignant tumors]. 1060 49

The p53 tumour suppressor induces cell cycle arrest and apoptosis in response to cellular stresses. p53 is inactivated by various cellular and viral factors. We set out to generate regulatable p53 derivatives that are highly inducible by synthetic ligands, escape inactivation and efficiently induce apoptosis. We have generated Ligand Inducible Chimeric Tumour Suppressors (LI-CTS), that are inactive unless provided with artificial ligands. They are resistant to inactivation, due to the replacement of domains that mediate p53 inhibition by heterologous sequences. LI-CTS are activated by micromolar concentrations of ligand in a variety of cell lines. Following ligand addition, they translocate to the nucleus, activate p53 inducible genes and induce apoptosis. We have established human head and neck squamous cell carcinoma lines that stably express LI-CTS, which are inducible. These lines form tumours in nude mice in the absence of ligand. Addition of ligand inhibits tumour formation, and moreover, regresses established tumours by apoptosis. Although regulatable p53 expression has been achieved previously, our study provides the first demonstration of regulatable in vivo regression of tumours in a p53 based approach. Regulated inhibition and regression of tumours with a ligand inducible chimeric tumour suppressor could provide a novel approach to p53 based gene therapy.
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PMID:Tumour regression in a ligand inducible manner mediated by a chimeric tumour suppressor derived from p53. 1065 80

The aim of this study was to study the protein expression of six proto-oncogenes (epidermal growth factor receptor (EGFR), c-fms, c-myc, c-kit, c-erbB-2 and pan-ras) and one tumour suppressor gene (TP53), by immunohistochemical staining of normal cervical stratified squamous epithelium and cervical intra-epithelial neoplasia (CIN). Paraffin sections of 45 normal cervical specimens, 38 CIN grade one (CIN1), 37 CIN2 and 43 CIN3 were studied. An immunohistochemical (IHC) score was derived from the intensity of staining and the percentages of cells stained. In normal cervical specimens, a higher IHC score was found with EGFR and c-fms in superficial (S), intermediate (I) and parabasal (PB) cells compared with basal cells. In contrast, a higher IHC score was found with c-erbB-2 in basal cells in normal cervical specimens. Dysplastic cells in CIN had a higher IHC score with c-myc and c-erbB-2 than normal S/I and PB cells. Dysplastic cells had a higher score with EGFR than normal basal cells. However, a higher IHC score with EGFR and c-fms was found in normal S/I cells than dysplastic cells. These findings suggested that EGFR and c-fms were activated in more differentiated normal cells but were less active in less differentiated normal basal cells. However, EGFR was reactivated in dysplastic cells. Meanwhile, c-erbB-2 was activated in less differentiated normal basal cells and dysplastic cells, and was less active in differentiated normal cells. c-myc was activated in dysplastic cells. c-fms was more active in more differentiated normal cells and was not activated in less differentiated or dysplastic cells. c-kit, pan-ras and TP53 were not activated in normal nor dysplastic cervical cells. These results suggest EGFR, c-erbB-2 and c-myc may be important proto-oncogenes in CIN and that antibodies or anti-genes targeted against them may alter the progress of CIN to invasive cancer.
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PMID:Proto-oncogenes and p53 protein expression in normal cervical stratified squamous epithelium and cervical intra-epithelial neoplasia. 1067 85

Loss of heterozygosity (LOH) of chromosome arm 18q is frequent in gastrointestinal cancers. Over 90% of pancreatic carcinomas have 18q LOH. Bi-allelic inactivation of the MADH4/DPC4/SMAD4 gene at 18q21.1 is seen in about half of pancreatic carcinomas with 18q LOH. In the remaining tumors with 18q LOH, MADH4 is not mutated and its expression is unaffected, and no alterations in MADH2/SMAD2, a MADH4-related gene at 18q12.3, have been found. A controversial candidate tumor-suppressor gene at 18q21.2 is DCC (deleted in colorectal carcinoma), which encodes a netrin-1 receptor component with functions in cell migration and apoptosis. Reduced or absent DCC expression has been observed in many cancers, but few somatic mutations that would clearly inactivate DCC function have been reported. We studied a panel of 115 pancreatic and 14 biliary cancers for homozygous deletions of DCC exons and flanking 18q regions. Seven homozygous deletions were seen in the region that includes the DCC gene. In two tumors, the deletions inactivate DCC but not MADH4. A physical and transcript map of the deleted regions was constructed, and DCC was the only known gene affected by all seven deletions. These data are the strongest mutational evidence presented yet in support of the hypothesis that DCC or another gene in the region distal to MADH4 is inactivated, playing a causal role in cancer development.
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PMID:Homozygous deletions inactivate DCC, but not MADH4/DPC4/SMAD4, in a subset of pancreatic and biliary cancers. 1071 64

In Drosophila, genetic loss of the tumour suppressor protein Dlg (in dlg mutants) or p127 (in lgl mutants) leads to loss of epithelial structure and excess proliferation in the imaginal discs and brain of the developing larva. These phenotypes show most of the characteristic features of human neoplasia, so study of the gene products may contribute to our understanding of cancer. Both proteins occur in high molecular-mass complexes in the membrane-associated cytoskeleton, and they both appear to play dual roles as structural proteins and active partners in signal transduction. Dlg is a membrane-associated guanylate kinase homolog (MAGUK) found at septate junctions between epithelial cells, as well as at neuromuscular junctions. Specific domains of the protein are required for membrane targeting and for localisation injunctions, and for epithelial cell proliferation control; all of these functions are probably mediated through binding to other proteins. Loss of Dlg results in the absence of septate junctions, delocalisation of several proteins including Fasciclin III, Coracle, actin and tubulin, and loss of cell polarity. p127, although mostly associated with the plasma membrane, is in most cell types also present in the cytoplasm. It shows a dynamic subcellular distribution, and its cytosolic and membrane-associated forms play distinctive roles by interacting with different binding partners, in particular the non-muscle myosin II heavy chain. Defects associated with the lgl temperature-sensitive allele include loss of the columnar organisation of epithelial cells, indicating that p127 contributes to cell structure, presumably by stabilising the plasma membrane. In addition to their organising functions, both Dlg and p127 appear to be involved in signal transduction pathways. Study of these genes shows that some proteins play both structural and functional roles, and that cancer can involve changes in the organisation of signalling pathways in addition to changes in individual pathway components.
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PMID:What is Drosophila telling us about cancer? 1072 90

The FHIT gene is located at a chromosomal site (3p14.2) which is commonly affected by translocations and deletions in human neoplasia. Although FHIT alterations at the DNA and RNA level are frequent in many types of tumours, the biological and clinical significance of these changes is not clear. In this study we aimed at correlating loss of Fhit protein expression with a large number of molecular genetic and clinical parameters in a well-characterized cohort of non-small-cell lung cancers (NSCLCs). Paraffin sections of 99 non-small-cell carcinomas were reacted with an anti-Fhit polyclonal antibody in a standard immunohistochemical reaction. Abnormal cases were characterized by complete loss of cytoplasmic Fhit staining. The Fhit staining results were then correlated with previously obtained clinical and molecular data. Fifty-two of 99 tumours lacked cytoplasmic Fhit staining, with preserved reactivity in adjacent normal cells. Lack of Fhit staining correlated with: loss of heterozygosity (LOH) at the FHIT 3p14.2 locus, but not at other loci on 3p; squamous histology; LOH at 17p13 and 5q but not with LOH at multiple other suspected tumour suppressor gene loci; and was inversely correlated with codon 12 mutations in K-ras. Fhit expression was not correlated overall with a variety of clinical parameters including survival and was not associated with abnormalities of immunohistochemical expression of p53, RB, and p16. All of these findings are consistent with loss of Fhit protein expression being as frequent an abnormality in lung cancer pathogenesis as are p53 and p16 protein abnormalities and that such loss occurs independently of the commitment to the metastatic state and of most other molecular abnormalities.
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PMID:Loss of Fhit expression in non-small-cell lung cancer: correlation with molecular genetic abnormalities and clinicopathological features. 1073 5

Germline PTEN mutations cause Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR), two hamartoma-tumour syndromes, and somatic PTEN alterations have been shown to participate, to a greater or lesser extent, in a wide variety of sporadic neoplasia. PTEN is a tumour suppressor and dual-specificity phosphatase which affects apoptosis via its lipid phosphatase activity in the phosphoinositol-3-kinase and AKT pathway as well as inhibiting cell spreading via the focal adhesion kinase pathway. CS and BRR share some features, such as hamartomas and lipomatosis. To determine whether other syndromes characterized by overgrowth and lipomas are part of the PTEN syndrome spectrum, we ascertained six individuals with overgrowth and lipomas but who did not meet the diagnostic criteria for CS or BRR. Five had Proteus syndrome and one, a Proteus-like syndrome. When germline DNA and DNA from at least one involved tissue per case were examined for PTEN mutations, only the Proteus-like patient was found to harbour a germline R335X mutation. Interestingly, a lipomatous mass, an epidermoid naevus and arteriovenous malformation tissue, all of which were sampled from physically distinct sites, were all found to carry a second hit R130X mutation on the allele opposite the germline R335X. Both mutations have been described in CS and BRR. We postulate that the second hit, R130X, occurred early in embryonic development and may even represent germline mosaicism. Thus, PTEN may be involved in Proteus-like syndrome with its implications for cancer development in the future.
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PMID:Germline and germline mosaic PTEN mutations associated with a Proteus-like syndrome of hemihypertrophy, lower limb asymmetry, arteriovenous malformations and lipomatosis. 1074 83

Mutation of p53, a tumour suppressor gene, is uncommon in cervical cancer but the detection of human papillomavirus (HPV) DNA in cervical cancer is common. The findings of increased susceptibility to degradation of p53 by E6 protein of HPV16/18 in cervical cancer with homozygous arginine at codon 72 (HA72) of p53 led to this study on whether cervical cancers with HA72 were more aggressive with the increase in the rate of loss of p53 function. In 102 cervical cancers, 76.5% were HPV16/18 positive and 30% had HA72. No survival difference was detected between HA72 and non-HA72 tumours irrespective of HPV16/18 status. Furthermore, the detection of HPV16/18 in cervical cancer was found not to be of prognostic significance in this study.
Tumour Biol
PMID:Homozygous arginine at codon 72 of p53 has no prognostic significance in cervical cancer. 1075 63

The development of gastrointestinal cancer in humans and animals occurs through a consecutive series of stages termed initiation, promotion and progression. The characterization of each of these stages has been elucidated in several model systems as well as in human neoplasms. Both single, putatively initiated cells and preneoplastic foci have been identified by marker protein differences as well as by mutational changes. The promotion stage involves the clonal expansion of single initiated cells. Such expansion can be rapidly reversed by a variety of means, of which acute fasting (as exemplified in rat hepatocarcinogenesis) is among the most rapid and efficient. This reversal involves a selective apoptosis of preneoplastic cells and preneoplastic lesions, associated with a marked increase in expression of the proto-oncogene c-myc. Transition of cells from the stage of promotion to that of progression initially involves specific karyotypic alterations, as noted in both the rat liver model and human colon carcinogenesis. In the former, the transition appears to be associated with enhanced expression of the H119 imprinted putative tumour suppressor gene. Thus, the use of model systems may be applied directly to the human circumstance, increasing the potential both for rational prevention of gastrointestinal neoplasia and for new approaches to the therapy of neoplastic disease in the progression stage.
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PMID:Review article: the stages of gastrointestinal carcinogenesis--application of rodent models to human disease. 1080 17


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