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)

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.
Eur J Cancer B Oral Oncol 1992 Jul
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

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

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.
Eur J Cancer B Oral Oncol 1992 Oct
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

The molecular basis of cancer is now understood to involve activation of dominant oncogenes and inactivation of tumour suppressor genes, and these genetic events may represent novel targets for cancer therapy. This review focuses on the potential use and ethical implications of gene transfer to alter the behaviour of somatic cells in cancer patients. Antisense nucleic acids and ribozymes represent informational drugs that may be used to modulate the expression of selected genes and suppress malignant behaviour in cancer cells. Genetic immunomodulation by introducing genes for cytokines into cancer cells or lymphocytes can stimulate a cytotoxic immune response against the tumour. Gene transfer techniques can be applied to target prodrug activation specifically to tumour cells and also to protect normal tissues against toxic chemotherapy. Gene replacement therapy could even be used to restore the function of defective tumour suppressor genes.
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PMID:Gene therapy for cancer. 134 18

Mutations in the p53 gene are the commonest specific genetic change in human cancer. In normal tissues, p53 protein is present in such low quantities that it is not readily detectable by immunochemical techniques. However, in many tumour cells large amounts of p53 protein accumulate and can be seen by simple immunohistochemical staining; this is generally attributed to the accumulation of stabilised, mutant protein. We have found a mother and daughter, who both have a history of breast cancer, who show strong immunohistochemical staining of p53 in most of their normal epithelial and mesenchymal cells. Their family has a history of multiple cancers developing at an early age. Detailed protein analysis and gene sequencing of material obtained from cultured cells, grown from a skin biopsy taken from the daughter, suggest that her cells contained large quantities of normal (unmutated) p53. We suggest that this phenotype defines a new inherited cancer susceptibility syndrome that is distinct from the germ-line mutations in p53 found in some Li-Fraumeni families. This new syndrome affects p53 tumour suppressor function through an indirect mechanism that stabilises normal p53. It remains to be established whether this mechanism also contributes to the accumulation of p53 in sporadic cancers.
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PMID:Abnormal expression of wild type p53 protein in normal cells of a cancer family patient. 135 90

There is now ample genetic and some functional evidence for the existence of tumour suppressor genes. Although much of the functional evidence has been derived from somatic cell hybrid and chromosome transfer studies, it is critical that cloned candidate tumour suppressor genes be used in such functional assays. Our experience with RB and p53 indicates that much will be learned about the control of the cell cycle from studies of tumour suppressor genes. However, the handful of candidate genes cloned to date also indicates a variety of cellular localizations and cellular functions. Thus, just as oncogenes seem to act to promote growth at many levels of metabolic control, it would seem that tumour suppressor genes act in complementary ways to control cell proliferation. The molecular genetic study of cancer has truly entered an exciting phase.
Cancer Surv 1992
PMID:Functional evidence for human tumour suppressor genes: chromosome and molecular genetic studies. 135 13

We develop a mathematical model for the initial growth of a tumour after a mutation in which either an oncogene is expressed or an anti-oncogene (i.e. tumour suppressor gene) is lost. Our model incorporates mitotic control by several biochemicals, with quite different regulatory characteristics, and we consider mutations affecting the cellular response to these control mechanisms. Our mathematical representation of these mutations reflects the current understanding of the roles of oncogenes and anti-oncogenes in controlling cell proliferation. Numerical solutions of our model, for biologically relevant parameter values, show that the different types of mutations have quite different effects. Mutations affecting the cell response to chemical regulators, or resulting in autonomy from such regulators, cause an advancing wave of tumour cells and a receding wave of normal cells. By contrast, mutations affecting the production of a mitotic regulator cause a slow localized increase in the numbers of both normal and mutant cells. We extend our model to investigate the possible effects of an immune response to cancer by including a first order removal of mutant cells. When this removal rate exceeds a critical value, the immune system can suppress tumour growth; we derive an expression for this critical value as a function of the parameters characterizing the mutation. Our results suggest that the effectiveness of the immune response after an oncogenic mutation depends crucially on the way in which the mutation affects the biochemical control of cell division.
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PMID:Oncogenes, anti-oncogenes and the immune response to cancer: a mathematical model. 135 64

Fifty-nine primary breast carcinomas and 11 metastases were examined to identify genetic alterations in the tumour suppressor gene regions 3p, 11p, 13q, 17p, and 17q. Loss of heterozygosity (LOH) was frequently observed on chromosome arms 17p (p144D6 lost in 75%, pYNZ22.1 in 55%, and TP53 in 48% of the primary tumours), 13q (RBI lost in 40% of the primary tumours), and 17q (pRMU3 lost in 35%, pTHH59 in 29%, and NM23HI in 26% of the primary tumours). Loss of all the markers except p144D6 was observed even more frequently in the metastases. Pairwise comparisons for concordance of allele losses on 17p indicated that there might be two genes on 17p implicated in breast cancer development; the TP53 gene and a gene located close to the p144D6 and pYNZ22.1 markers. LOH of the RBI gene was associated with LOH of pYNZ22.1 and p144D6, but not with LOH of TP53. LOH of RBI and TP53 was associated with occurrence of ductal carcinomas, RBI and p144D6 losses with tumour size, and p144D6 losses with positive node status as well. LOH of TP53 and the three 17q markers NM23HI, pTHH59, and pRMU3 was most frequently observed in tumours from postmenopausal women. p144D6 losses occurred most frequently in progesterone receptor-negative tumours, whereas pTHH59 losses occurred most frequently in oestrogen receptor-negative tumours. LOH of the investigated loci was not associated with ERBB2 protooncogene amplification, with positive family history of breast cancer, or with survival.
Genes Chromosomes Cancer 1992 Mar
PMID:Genetic alterations of the tumour suppressor gene regions 3p, 11p, 13q, 17p, and 17q in human breast carcinomas. 137 10


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