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)

Genetic and molecular analyses of Drosophila have shown that tumorigenesis may arise from inactivation of single genes controlling cell growth and differentiation. Recessive mutations in a series of genes interrupt the differentiation of primordial cells and result in overgrowth, producing either hyperplasia or neoplasia. In mutant animals tumours form in either the optic centres of the larval brain, the imaginal discs or the haemopoietic organs. In Drosophila 17 genetic loci giving rise to neoplasia and six loci producing hyperplasia have been identified. The lethal(2)giant larvae gene constitutes the prototype of these genes. Its molecular cloning and analysis have demonstrated that the tumor phenotype results from a lack of gene function. Furthermore, tumour prevention was achieved by introducing a normal copy of l(2)gl into the genome of l(2)gl- deficient animals, showing that the l(2)gl gene behaves as a tumour suppressor or anti-oncogene. Melanomas of genetic origin develop in interspecies hybrids of the fish Xiphophorus. The melanoma appears when a sex linked chromosomal gene (Tu) is present among the progeny animals lacking an autosomal locus Differentiation, which acts as a tumour suppressor gene. A sequence homologous to the erb-B gene can be associated to the sex chromosomal Tu locus. This gene encodes a receptor tyrosine kinase related to the EGF-receptor, and its activation and overexpression are thought to play a critical part in melanoma formation.
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PMID:The fruit fly Drosophila and the fish Xiphophorus as model systems for cancer studies. 210 23

The genetic factors involved in the multistep process of carcinogenesis can be divided at least into two major categories: 1. Mutated or lost genes, which may directly represent one step in the sequential process (tumour suppressor genes); inheritance of one tumour suppressor gene causes dominant expression of the carcinogenic phenotype (the dominant inheritance is described in the accompanying paper); 2. Other genes, which lead to conditions that favour the development of cancer and generally are inherited in a recessive fashion; they are the subject of this paper. Autosomal recessively inherited diseases, such as xeroderma pigmentosum, ataxia-telangiectasia, Bloom's syndrome and Fanconi's anaemia display increased genome instability (chromosomal fragility and/or DNA-repair deficiencies) and are associated in the homozygote and probably also in the heterozygote state with defined malignancies. Neoplasms particularly of the lymphoreticular system frequently occur in patients with genetically determined immunodeficiencies (e.g. severe combined immune deficiency or Wiskott-Aldrich syndrome). People differ due to their individual genetic constitution in their responses to various classes of carcinogens such as physical and chemical agents, to dietary habits, as well as to viruses. Furthermore, tumours are often found in patients displaying premature aging (e.g. Werner's syndrome). In addition, several metabolic abnormalities such as genetic syndromes featuring chronic liver disease, but also many other inherited metabolic conditions have cancer as a regular or frequent complication.
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PMID:Recessively inherited deficiencies predisposing to cancer. 219 May 29

Tumour and blood leucocyte DNA from a consecutive series of patients with primary breast cancer was probed to detect deletions at six polymorphic loci in tumour tissue. The highest frequency of allele loss (61%) was found with the probe YNZ22, which detects a sequence on the short arm of chromosome 17 (at p13.3). The previously reported loss of alleles at the Harvey ras locus (11p14) in about 20% of breast tumours was confirmed. The putative breast tumour suppressor gene on 17p may be the same as that already noted for colon and lung cancers and it is suggested that deletion of this gene is one of a cumulative series of lesions involving genetic changes in the evolution of breast cancer. The findings identify chromosome 17p as a candidate region for linkage studies in breast cancer families.
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PMID:Allele loss on short arm of chromosome 17 in breast cancers. 290 22

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 present study describes mutations of the tumour suppressor gene p53 in a local collection of colorectal and hepatocellular carcinomas (HCCs). Tumour DNA was extracted from both fresh and paraffin-embedded tissues and exons 5-8 of the p53 gene were amplified by polymerase chain reaction (PCR). Mutations were detected by single-strand conformation polymorphism (SSCP) analysis followed by direct DNA sequencing. Of the 38 colorectal carcinomas and 42 HCCs examined, 15 (39%) and 13 (31%), respectively, showed p53 mutations. Two-thirds (10/15) of the mutations in colorectal carcinomas were base transitions with a predominance at CpG dinucleotide sites--a pattern characteristic to an endogenous process in cancer development. Three mutational hotspots at codons 175, 248 and 282 were also identified. Mutations did not correlate with histological grade, Dukes stage, or metastasis. However, tumours at the distal site of the colorectum showed a higher proportion of mutations than the proximal site. In the case of HCCs, majority (9/13) of the mutations were base transitions and no mutations were observed at codon 249. This is in contrast to results from other high-incidence areas such as Africa and China, where aflatoxin is believed to be a major aetiologic factor for liver cancers. The results therefore suggest that other risk factors, rather than dietary exposure to aflatoxin, may contribute to the high HCC incidence in Singapore.
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PMID:Mutations of the tumour suppressor gene p53 in colorectal and hepatocellular carcinomas. 765 61

Tumour-suppressor genes are negative regulators of cell division and growth. Over the past decade, multiple, distinct tumour-suppressor genes have been identified and cloned. In recent years, the ability to specifically manipulate the mouse genome via overexpression, underexpression or deletion of genes using transgenic expression systems and embryonic stem cell (ES) technology has led to the identification and definition of the precise function of several tumour suppressor genes in vivo. Included in this group are mice with mutations in the p53 and retinoblastoma (Rb) genes. p53 Mutant mice are highly susceptible to tumour development and will serve as excellent models to understand the aetiology and pathology of several human cancers. In contrast to the role of the Rb gene in human retinoblastomas, mice heterozygous for a mutant Rb allele do not develop retinoblastoma, but develop pituitary tumours instead. Similar ES cell technology has been used to generate alpha-inhibin deficient mice. Inhibin-deficient mice develop gonadal and adrenal tumours with nearly 100% penetrance. These studies have identified inhibin as a novel secreted tumour suppressor. In the future, many of the unidentified functions of tumour-suppressor genes can be tested using this powerful in vivo assay system.
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PMID:Transgenic mouse models for tumour-suppressor genes. 767 52

Colorectal cancer (CRC) develops through several histologically well-defined stages, reflecting the sequential acquisition of genetic alterations. Several frequently mutated genes have been identified which probably contribute to the development of both hereditary and sporadic cancer (reviewed in Bishop and Thomas, 1990; Fearon and Vogelstein, 1990; Fearon and Jones, 1992; Hamilton, 1992). Several generalizations emerge from this work. Mutations are observed in the earliest detectable stages of cancer development. Specific genes tend to be mutated in a given order, but it is the accumulation of a critical number of lesions which governs the appearance of neoplasia. Mutations actively promote neoplastic character by activating oncogenes and eliminate restraints on neoplastic character by inactivating tumour suppressor genes.
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PMID:Genetics, molecular biology and colorectal cancer. 769 96

The development of cancer is a multistep process involving accumulation of genetic changes which progressively transform normal cells to neoplastic cells. During the last few years, our understanding and knowledge of the genetic changes involved in ovarian carcinogenesis have increased dramatically. In this review I will focus on karyotypic abnormalities in ovarian cancer and will also refer to molecular studies involving alterations in oncogenes and tumour suppressor genes in ovarian tumorigenesis. Cytogenetic analyses have identified two distinct subgroups. Simple karyotypic changes, trisomy 12 being the most common aberration in this group, are recurrently found in well differentiated ovarian carcinomas. Complex karyotypic abnormalities, including predominantly chromosome losses, deletions and unbalanced translocations, are found in moderately and poorly differentiated carcinomas. The bands and regions most commonly involved in structural rearrangements have been, in decreasing order of frequency, 19p13, 1p36, 1q21, 1q23-25, 3p11-13, 6q21, 19q13, 11p13-15, 11q13, 11q23, 12q24, 12p11-13, and 7p13-22. The finding of identical karyotypic and other genetic changes in tumour samples taken from different sites, such as tumours from both ovaries and omental metastases, indicate that ovarian cancer is of unicentric origin with subsequent metastatic spread giving rise to multiple implants. Molecular genetic changes important in ovarian cancer involve both classes of tumor-associated genes: RAS activation is generally not observed in ovarian cancer. Alterations of MYC1, ERBB2, AKT2, TP53 has been described in some ovarian carcinomas. The temporal relationship of these mutations, i.e. early or late events in ovarian carcinogenesis, remains to be determined.
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PMID:Genetic changes in ovarian cancer. 774 4

Activation of the c-myc oncogene and functional loss of the p53 tumour suppressor gene are among the most frequently recorded genetic lesions in neoplasia but their combined effect has not previously been investigated. By breeding together mice transgenic for human c-myc (CD2-myc) and mice carrying an inactive p53 allele (p53-/-) we found that these genetic lesions act synergistically in vivo. Offspring carrying the CD2-myc transgene and the homozygous p53 null mutation (p53-/-/CD2-myc) were viable but developed thymic lymphomas with dramatically increased frequency and reduced latency compared to both parental groups. The tumour phenotype was similar to that previously recorded for CD2-myc mice (predominantly CD3+, CD4+8+) but tumour clonal complexity and metastasis was significantly greater in the p53-/-/CD2-myc mice. In contrast, no significant increase in tumour incidence was seen in p53+/-/CD2-myc vs p53+/+/CD2-myc mice over a 6 month observation period. However, the loss of wild type p53 in a proportion of tumour cells in p53+/-/CD2-myc lymphomas suggests that wild type allele loss can occur as a late progression step rather than an initiating step in these tumours. We suggest that p53 loss of function may collaborate with the CD2-myc transgene at more than one stage in thymic lymphoma development.
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PMID:Synergy between a human c-myc transgene and p53 null genotype in murine thymic lymphomas: contrasting effects of homozygous and heterozygous p53 loss. 775 48

The tumorigenesis of neuroendocrine tumours remains poorly understood, although a minority, the familial multiple endocrine neoplasia (MEN 1 and MEN 2), are known to be of uncommon genetic origin. Mutation of the tumour suppressor gene, p53, is now known to be a common genetic alteration in about half of all types of non-endocrine cancers. In the present study, immunocytochemistry using the monoclonal anti-p53 antibody, DO-7, has been employed to investigate the accumulation of p53 immunoreactivity in a wide range of primary neuroendocrine tumours. Tumours (n = 109) were fixed and processed to paraffin wax according to a constant protocol. Sections were subjected to microwave antigen retrieval prior to immunostaining for p53. Positive nuclear immunostaining was observed in one medullary carcinoma of the thyroid (MCT), one lung carcinoid, and five small cell carcinomas of the lung (SCCL). All other tumour samples were consistently negative. As the neoplasia investigated in this study comprised a wide spectrum of neuroendocrine tumour types and ranged from minute, relatively benign lesions to malignant metastasizing disease and as there was no relationship between the presence of p53 overexpression and clinico-pathological features, the present study suggests that p53 gene mutation may be relatively unimportant in the genesis of neuroendocrine tumours.
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PMID:Overexpression of the tumour suppressor gene p53 is not implicated in neuroendocrine tumour carcinogenesis. 877 44


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