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)

Retinoblastoma, the most common intraocular malignancy of children, has served as an important paradigm for understanding the events involved in neoplastic transformation. Much of the contemporary molecular description of human cancers stems directly from experimental approaches first developed to study this childhood tumour. This analytical methodology has demonstrated a major role for heritable predisposition in tumourigenesis, provided evidence for tissue pleiotropy of cancer genes, and revealed a more precise estimation of the number, activity, and location of other tumour suppressor loci.
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PMID:Molecular genetics in the pathology and diagnosis of retinoblastoma. 166 90

Mutations in a human homologue of the yeast DNA mismatch repair gene MSH2 (equivalent to bacterial MutS) cause the condition hereditary non-polyposis colorectal cancer (HNPCC). Cancers in HNPCC originate within benign neoplastic polyps termed adenomas. Adenomas are clonal and each may serve as a marker of a single initiating mutation. The progression of adenomas is marked by increasing size, dysplasia and villosity. These characteristics can be taken as the morphological counterparts of the stepwise accumulation of mutations implicating oncogenes and tumour suppressor genes. The aim of this study was to link the morphogenesis of hereditary colorectal cancer with recent insights into the role of DNA mismatch repair genes. The frequency and anatomical distribution of adenomas in at-risk members of HNPCC families was the same as in an autopsy population. This suggests that the HNPCC gene does not initiate the process of neoplastic transformation. On the other hand, adenomas in at-risk members of HNPCC families were more likely to show villosity (p < 0.001), high grade dysplasia (p = 0.002) and probably increased size (p = 0.15). These findings are consistent with the observation that the HNPCC gene causes DNA replication errors to develop and accumulate within neoplastic but not normal tissues. The effect of the HNPCC gene is to accelerate the progression of adenoma to carcinoma, but not to initiate adenoma development.
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PMID:Hereditary non-polyposis colorectal cancer--morphologies, genes and mutations. 752 76

We report a clinical case of a double primitive tumour (right kidney clear cell carcinoma and gastric carcinoma) in two brothers. There is no history of cancer in the parents. Both patients were previously affected by gastric ulcer. No report of association between the two neoplasms was found in literature. The age of the patients (61 and 70 years) and the singleness of the kidney tumour seem to exclude the case of a familial kidney cancer. The neoplastic transformation of the gastric ulcer is instead a quite frequent report with an incidence of about 1%. Alterations of oncogenes or tumour suppressor genes shared from both neoplasm are at present still unknown. Nevertheless molecular analysis of patients' neoplastic genome could point out typical chromosome translocations/deletions or gene mutations.
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PMID:[Appearance in 2 brothers of double primary neoplasms: right renal carcinoma and gastric adenocarcinoma]. 757 Feb 61

The probability of a mouse cell becoming fully transformed in vivo or in vitro is enormously greater than that of a human cell. The number of events in tumour progression is similar in rodent and human cells, and it is unlikely that the difference in neoplastic transformation frequency can be explained on the basis of gene mutation in oncogenes and tumour suppressor genes. Instead, it is proposed that mouse cells may be (a) more subject to destabilization of the karyotype, (b) have less efficient check point cell cycle controls after DNA is damaged and/or (c) have less stringent epigenetic controls of gene activity, based on DNA methylation. Much evidence exists that mouse or rat cells are less efficient in DNA repair, maintenance of DNA methylation and other aspects of DNA metabolism. These relate to the difference in longevity in these and other mammalian species. Ageing is likely to be due to the failure of cell and tissue maintenance. Long lived species invest more in various somatic maintenance mechanisms than do short lived ones, and this includes protection against neoplastic transformation. The future study of the basis of the difference between human and mouse or rat cells in resistance to transformation is likely to yield important insights into the sequential events in tumour progression.
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PMID:Neoplastic transformation: the contrasting stability of human and mouse cells. 897 31

HeLa x skin fibroblast human hybrid cells have been developed into a model of radiation-induced neoplastic transformation. The authors' studies indicate that the loss of putative tumour suppressor loci on fibroblast chromosomes 11 and 14 is evident after radiation-induced neoplastic transformation. How these fibroblast chromosomes/putative tumour suppressor loci are lost after radiation exposure is currently being investigated. It has been shown that the appearance of transformed foci correlates with the onset of the delayed reduction in plating efficiency or delayed death. This delayed death appears to be the result of the onset of a novel delayed apoptosis in the irradiated progeny beginning around day 8 post-irradiation. It was proposed that the reduction in plating efficiency and subsequent neoplastic transformation are all the result of a radiation-induced genomic instability. The instability process has two relevant outcomes: (1) cell death due to the induction of a delayed apoptosis in cells; and (2) neoplastic transformation of a small subset of survivors that have lost fibroblast chromosomes 11 and 14 (tumour suppressor loci) but either have not acquired enough genetic damage to induce the apoptotic response or have undergone molecular changes allowing them to bypass apoptosis. Data from the genomic instability and delayed death literature will be reviewed in terms of relevance to radiation-induced neoplastic transformation. New data are presented which demonstrate that use of growth media supplemented with a specific lot of calf serum was found to increase the number of cells undergoing radiation-induced neoplastic transformation, compared with standard serum after a fixed dose of radiation. This correlates with an increase in delayed death in the irradiated progeny which the authors propose is the result of increased genomic instability post-irradiation of cells grown in this serum. Preliminary data are presented indicating that a delayed apoptosis is also seen after high-energy He- particle exposure in this system.
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PMID:Evidence for a role of delayed death and genomic instability in radiation-induced neoplastic transformation of human hybrid cells. 988 21

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

Cancer is generally believed to arise from a single cell which has become 'initiated' by mutation of a few crucial genes, caused by random 'hits' in its DNA, a 'hit' being an error in DNA replication or a reaction of the DNA with free radicals or other chemical species of exogenous or endogenous origin. It is not obvious how the epidemiological data on cancer incidence can be interpreted within the framework of this paradigm. For example, it cannot account quantitatively for the age dependence of cancer incidence, or for the fact that the incidence of cancer in people with hereditary mutations in tumour suppressor genes is much lower than expected, or for the observation that while in some types of cancer, like colon and pancreas, certain highly oncogenic mutations, such as that of TP53, are prevalent, there is no significant increase in the incidence of these cancers in people who carry the mutations by heredity. It is argued here that although mutations in such genes appear to be of crucial importance in carcinogenesis they may not be the rate limiting events in common cancer. The epidemiological data are consistent with the hypothesis that the rate limiting processes involve large numbers of cells. Conceivably, the mutations directly underlying neoplastic transformation may be the result of a local collapse in the system of intercellular processes on which the stability of the normal genotype and phenotype depends, and thereby trigger a cascade of mutations, among them the highly oncogenic ones. This local collapse may be due to mutations of many different genes in many cells as well as to other factors affecting the integrity of tissue.
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PMID:The origin of oncogenic mutations: where is the primary damage? 1102 32

Several recent advances have been made in our understanding of the pathogenesis of endometrial tumours, particularly endometrioid endometrial carcinoma (EEC). Mutations in the PTEN gene and microsatellite instability (MSI) are common genetic abnormalities in EECs, and distinguish these lesions from other histological subtypes of endometrial carcinoma. Endometrial precancers are monoclonal lesions that share a common genetic lineage with invasive EEC, including PTEN mutations and MSI. Mutations of the PTEN tumour suppressor gene have been identified in histologically normal-appearing endometrium exposed to oestrogen, 18-55% of endometrial precancers and 26-80% of EECs. PTEN has been shown to play several roles in tumour suppression, including cell cycle arrest and promotion of apoptosis. Loss of PTEN function predisposes endometrial cells to neoplastic transformation, particularly in high-oestrogenic states. MSI is another common alteration seen in EECs and endometrial precancers, and some studies have reported an association between MSI and PTEN mutations. The replication error that results in MSI may facilitate the development of PTEN mutations in some, but not all, cases of EEC. The prognostic significance of PTEN gene mutations and MSI in endometrial carcinoma is controversial. Further study is needed to delineate the different pathogenetic pathways of EEC and their natural history.
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PMID:PTEN mutations and evolving concepts in endometrial neoplasia. 1180 78

In mammalian cells, neoplastic transformation is directly associated with the expression of oncogenes, loss or simple inactivation of the function of tumour suppressor genes and the production of certain growth factors. Genes for suppression of the development of the neoplastic cellular immunophenotype, as well as inhibitory growth factors, have regulatory functions within the normal processes of cell division and differentiation. Telomerase (a ribonucleoprotein polymerase) activation is frequently detected in various neoplasms. Telomerase activation is regarded as essential for cell immortalisation and its inhibition may result in spontaneous regression of neoplasms. This phenomenon of neoplasms occurs when the malignant tissue mass partially or completely disappears without any treatment or as a result of a therapy considered inadequate to influence systemic neoplastic growth. This definition makes it clear that the term 'spontaneous regression' applies to neoplasms in which the overall malignant disease is not necessarily cured and to cases where the regression may not be complete or permanent. A number of possible mechanisms of spontaneous regression are reviewed, with the understanding that no single mechanism can completely account for this phenomenon. The application of the newest immunological, molecular biological and genetic insights for more individualised and adequate antineoplastic immunotherapy (alternative biotherapy) is also discussed.
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PMID:Spontaneous regression of neoplasms: new possibilities for immunotherapy. 1207 83

The ARF tumour suppressor protein (p14(ARF) in human and p19(ARF) in mouse) is a major mediator of the activation of p53 in response to oncogenic stress. Little is known about the signalling pathways connecting oncogenic stimuli to the activation of ARF. Regulation of ARF occurs primarily at the transcriptional level and several modulators of ARF transcription have been identified. Notably, ectopic expression of E2F1 upregulates ARF transcriptionally, and both E2F1 and ARF have been implicated in apoptosis and cell-cycle arrest. We have used primary mouse fibroblasts deficient for E2F1, E2F2, or both to determine the possible role of these E2F proteins as upstream regulators of ARF in response to oncogenic stimuli and other stresses. In particular, we have studied the effects of oncogenic Ras and the viral oncoprotein E1A on ARF levels, neoplastic transformation, and sensitization to apoptosis. We have also examined the behaviour of the E2F-deficient MEFs with respect to immortalization and sensitivity to DNA damage. None of the ARF-mediated responses that we have analysed is significantly affected in E2F1(-/-), E2F2(-/-) or E2F1/2(-/-) MEFs, and ARF is upregulated normally in all cases. Taken together, our results indicate that the activation of ARF in response to oncogenic stress can occur by E2F1- and E2F2-independent mechanisms. This challenges previous suggestions implicating E2F factors as key mediators in the activation of ARF by oncogenic stress.
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PMID:Activation of ARF by oncogenic stress in mouse fibroblasts is independent of E2F1 and E2F2. 1208 24


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