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)

In the last ten years considerable progress has been made in small-cell lung carcinoma (SCLC) biology, along with the technical progress made in molecular biology. This progress now allows us to propose a model for the genesis and the development of this type of tumor. Tobacco, the principal causal factor plays a dual role. In bringing about secretion of growth factors by the bronchial epithelia, usually involved in the normal development of lungs, and by functioning autocrinally and paracrinally, it facilitates the occurrence of mitotic mutations. Without directly contributing to cellular transformation, this autocrine functioning also gives a selective advantage to cells going through transformation or immortalization. The procarcinogenic or carcinogenic agents contained in tobacco smoke, whose level of production could be genetically determined, would also contribute to the accumulation of mutations affecting both suppressor genes and oncogenes. Two tumour suppressor genes have been identified: RB1 and P53. At least one other putative tumour suppressor gene has constantly been implied. It lies on the short arm of chromosome 3. There could also be the possibility of detecting subjects susceptible to developing an SCLC, a functional hemizygote still needing evaluation. The activated oncogenes principally belongs to the myc family. Their activation could correspond with the appearance of cellular clones having aggressive behavior independent of growth factors, chemoresistant and more metastatic. SCLC may be distinguished from other malignant lung tumors by a fairly characteristic pattern consisting of the loss of suppressor genes and the activation of oncogenes. The links between the neuroendocrine properties of this type of tumor and its characteristic description are being clarified and will contribute to a better understanding of the relationship between the different types of lung tumors. From this biologic knowledge follow several therapeutic applications under investigation (blocking autocrine loop through anti-GRP antibodies), as well as potential applications (concerning the products of suppressor genes) and possible applications such as prevention oriented towards detection of high-risk subjects.
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PMID:[Biology of small-cell bronchogenic carcinoma: recent advances]. 132 50

Lymphocyte activation requires signal transduction mediated by reversible phosphorylation. Changing profiles of phosphorylated intermediates relate to the progressive series of transduction pathways in cells moving from G0 to G1, and thereafter through the cell cycle. We have previously shown that transient inhibition of the serine/threonine protein phosphatases PP1 and PP2A by okadaic acid enhances early mitogenic stimulation. Thus target proteins of PP1/PP2A may be involved in regulation of early mitogenic signalling, with the phosphorylated form(s) being associated with signal enhancement. Later, pathways require dephosphorylation of these proteins, since continuous treatment with okadaic acid blocks lymphocyte progression through the cell cycle. Delayed addition of okadaic acid showed that this blockade occurs between 8 and 24 hr. Here we have furthered these observations to the level of gene induction by measuring messenger RNA (mRNA) levels for the following proteins: interleukin-2 (IL-2) and IL-2R alpha; p53, a tumour suppressor protein; the transcription factor krox-24; and two mediators of protein folding, namely cyclophilin and the heat-shock protein hsc70. An external standard was used to quantitate the mRNA levels per cell. We found that 24 hr exposure to okadaic acid has a general suppressive effect on concanavalin A (Con A)-stimulated gene induction. However, at 4 hr okadaic acid enhanced IL-2 mRNA levels induced by Con A. Moreover, in unstimulated lymphocytes, okadaic acid caused the induction of krox-24, indicating a role for PP1 and PP2A in the regulation of this gene in resting cells.
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PMID:Inhibition of the serine/threonine protein phosphatases PP1 and PP2A in lymphocytes: effect on mRNA levels for interleukin-2, IL-2R alpha, krox-24, p53, hsc70 and cyclophilin. 132 40

Cancer is now considered to be a multi-hit process which involves a number of aberrant genetic events culminating in malignant transformation. In squamous cell carcinoma (SCC) of the head and neck the action of both oncogenes and tumour-suppressor genes has been identified during the course of the disease. Cytogenetic analysis of these carcinomas has demonstrated chromosomal breakpoints, particularly in the regions of 1p22 and 11q13 together with frequent amplification of the proto-oncogenes in the 11q13 amplicon; int-2, hst-1 and bcl-1. Ras mutations have been infrequently identified in the Western World whereas ras over-expression has been a common finding and may be associated with the early development of head and neck cancer. C-myc over-expression appears to correlate with a poor prognosis for these patients. The tumour-suppressor gene p53 is also thought to be involved in the development of SCC in head and neck tumours and its aberrant expression is associated with a history of heavy smoking and heavy drinking. E-cadherin, a putative tumour-suppressor gene is down-regulated in poorly differentiated head and neck SCC and maybe important in nodal metastasis. A recent study has indicated that the Human Papilloma Virus (HPV 16 and 33) has a role in the aetiology of tonsillar carcinomas and HPV has been shown to produce transforming proteins which bind to and inactivate the p53 tumour suppressor gene. This evidence suggests that the possibility of a viral mechanism for the development of SCC in the head and neck should be considered. This paper proposes a series of genetic events to explain the development of SCC of the head and neck.
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PMID:Oncogenes and tumour-suppressor genes in squamous cell carcinoma of the head and neck. 133 Jan 49

One of the major debates in hepatocellular carcinogenesis at present is whether the hepatitis-B and -C viruses are directly carcinogenic or exert their effect indirectly by causing chronic necro-inflammatory hepatic disease, which in turn is responsible for malignant transformation of hepatocytes. This debate has been fueled by the observation that hepatitis C virus is a single-stranded RNA virus with no precedent for inducing cancer but with a marked propensity to cause chronic necro-inflammatory hepatic disease and by the findings in Chisari's transgenic mouse model, which suggest that severe and prolonged hepatocellular injury per se induces a proliferative response that progresses to tumour formation. Recent reports of a guanine to thymine mutation of the third base of codon 249 of the tumour suppressor gene, p53, in 50% of patients with hepatocellular carcinoma in regions of high aflatoxin exposure, and mutagenic experiments showing that aflatoxin B1 binds particularly to guanine residues in G-C-rich domains and that codon 249 is a preferred target have suggested a mechanism whereby aflatoxin might induce malignant transformation.
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PMID:Tumours of the liver. 133 85

Genes responsible for the hereditary predisposition to a variety of human cancers have now been isolated. Their function seems to be part of complex signalling pathways involved in the control of cellular differentiation and the cell cycle. The presence of a single copy of these genes appears to be sufficient to ensure normal development, i.e. prevents tumorigenesis, and has earned them the name--tumour suppressor genes.
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PMID:Tumour suppressor genes. 133 65

A series of 34 Wilms' tumours have been analysed for abnormal expression of the tumour suppressor gene p53 using frozen section immunohistochemistry. All tumours showed immunoreactivity with at least one of the specific antibodies used (monoclonal antibody PAb240, polyclonal antibodies CM1 and JG8). Abnormalities of p53 expression are very frequent in this type of childhood tumour.
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PMID:Aberrant expression of the tumour suppressor gene p53 is very frequent in Wilms' tumours. 133 42

The types of malignancy reported in carriers of constitutional ring chromosomes r(11), r(13), and r(22) are concordant with the chromosomal assignment of tumour suppressor loci associated with Wilms' tumour, retinoblastoma, and meningioma. It is suggested that the somatic instability of ring chromosomes may play a role in this association and that constitutional ring chromosomes may be a source for mapping of tumour suppressor loci with the potential for covering most or all of the human genome. The hypothesis predicts the presence of a locus on chromosome 10 associated with follicular carcinoma of the thyroid, in line with previous cytogenetic findings of rearrangements involving chromosome 10 in thyroid tumours, and a locus on chromosome 22 associated with testicular cancer. Development of neurofibromatoses (NF) that do not fulfil the clinical criteria of neurofibromatosis type 2 (NF2) in carriers with r(22) suggests either the presence of an additional NF locus on chromosome 22 or that ring chromosome mediated predisposition to somatic mutation of a specific tumour suppressor may be associated with atypical development of features usually associated with germline mutations.
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PMID:Constitutional ring chromosomes and tumour suppressor genes. 133 57

p53 tumour suppressor gene is often found mutated in Burkitt's lymphoma (BL) cell lines and tumours. We analysed 35 BL tumours for the accumulation of p53 protein, and correlated the results with DNA flow cytometric data on the proliferative activity (SPF), and data on the presence or absence of Epstein-Barr virus (EBV) DNA. More than one-third (37 per cent) of the tumours showed accumulation of p53, which was considered to be consistent with mutation of the p53 gene. Tumours that were positive both for EBV DNA and p53 had significantly higher mean SPF than corresponding EBV DNA negative and/or p53 negative tumours. The proportions of tumour cells with accumulation of p53 appeared to correlate with tumour SPF only in EBV DNA positive BLs. However, there was no apparent association between accumulation of p53 and the presence or absence of EBV DNA. These findings are suggestive of multiple pathways in BL tumour progression.
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PMID:Accumulation of p53 protein correlates with tumour proliferative activity in EBV positive Burkitt's lymphoma. 133 33

The linkage of herpes simplex virus (HSV) and human papillomavirus (HPV) to the development of oral cancer has been studied. In spite of the presence of viral nucleic acids in some human oral cancer specimens, HSV alone is not carcinogenic in animals: repeated viral inoculation to mouse or hamster oral mucosa fails to produce tumours or histopathological evidence of malignancy. However, HSV demonstrates co-carcinogenicity in vivo: viral inoculation significantly enhances the oncogenic capacity of chemical carcinogens in the oral cavity of mice and hamsters. Though the detailed mechanisms of HSV cocarcinogenicity are unknown, HSV promotes the chemical carcinogen-induced activation of certain cellular proto-oncogenes and inactivation of p53 tumour suppressor gene. Human papillomaviruses type 16 (HPV-16) and 18 (HPV-18) demonstrate oncogenicity by transforming normal human oral keratinocytes in vitro. While normal cells exhibit a limited life-span, cells transformed by these viruses show immortality and altered morphology in comparison with their normal counterparts. The HPV-immortalised cells contain multiple copies of intact viral genome integrated into cellular chromosomes. These cells also express several viral-specific mRNAs including viral E6/E7 mRNAs. Notably, these cells contain low levels of p53 protein and overexpressed cellular myc proto-oncogene compared to their normal counterpart; however, the immortilised cell lines are non-tumorigenic in nude mice.
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PMID:In vitro and animal studies of the role of viruses in oral carcinogenesis. 133 29

Deletions of chromosome 5 were initially reported as a consistently occurring chromosomal abnormality in 5q- syndrome. They have since been recognized to occur in other myeloid malignancies such as therapy-related leukaemia and de novo AML as well. The variability of the deletions, and the heterogeneity of the clinical syndromes, have made it difficult to describe a single clinical-molecular entity such as we see with chromosomal translocations described elsewhere in this volume. Translocations in leukaemogenesis often have a dominant effect leading to activation of oncogenes or the production of a modified protein. Consistently occurring chromosomal deletions in human tumours, however, have been regarded as evidence that the affected regions contain tumour suppressor genes. Loss of function of these tumour suppressor genes or 'recessive oncogenes' leads to cancer. Deletions in the long arm of chromosome 5 in myeloid malignancies are thought to signal the existence of a recessive oncogene on 5q, which is homozygously inactivated in these malignancies. Here we describe the clinical and molecular features of the diseases associated with deletions of chromosome 5 in an attempt to propose a unified approach to identifying the genes on 5q which are involved in leukaemogenesis. It is likely that the clinical heterogeneity of these disorders will not be understood until the relevant genes are cloned and their role in the initiation or progression of leukaemia is known.
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PMID:Myeloid malignancies and chromosome 5 deletions. 133 91


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