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)

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

Six families of activated protooncogenes, ras, raf, fur, neu, jun and myc have so far been associated with human lung cancer. Human bronchial epithelial cells in vitro are being used to investigate the functional role of these specific oncogenes and growth regulatory genes in carcinogenesis and tumour progression. When transferred into normal human bronchial epithelial cells by the highly efficient protoplast fusion method, the v-Ha-ras oncogene initiates a cascade of events leading to decreased responsiveness of these cells to inducers of squamous differentiation, aneuploidy and, less frequently, 'immortality' and tumorigenicity with metastasis in athymic nude mice. Transfection of the SV40 T antigen gene results in nontumorigenic cell lines that have a nearly normal pathway of terminal squamous differentiation and can be transformed into malignant cells by transfected Ha-ras, N-ras or Ki-ras. The combination of transfected c-myc and c-raf-1 also transforms human bronchial epithelial cells into neoplastic cells that exhibit some phenotypic traits found in small-cell carcinomas. These and other results indicate that proto-oncogenes dysregulate the pathways of growth and differentiation of human bronchial epithelial cells and play an important role in human carcinogenesis. Analyses of allelic deletion and somatic cell hybrids are being used to identify the chromosomal localization of tumour suppressor genes. We have examined 54 non-small-cell bronchogenic carcinomas with 13 polymorphic markers. Loss of heterozygosity was more frequent than among 23 squamous-cell carcinomas than among 23 adenocarcinomas or eight large-cell carcinomas. Loss of heterozygosity for chromosome 17p was found in 89% of cases of squamous-cell carcinoma and 18% of adenocarcinomas. Analysis of chromosome 11 for allelic deletions revealed two commonly deleted regions (11p13 and 11p15.5). Somatic cell hybrids between normal human bronchial epithelial cells and Hut292DM, a lung carcinoma cell line, had a finite lifespan in vitro and were nontumorigenic in athymic nude mice. Tumour suppressive effects of individual or combinations of specific human chromosomes on Hut292DM are being examined by formation of microcell-cell hybrids. Chromosome 11 has tumour suppressor activity in these hybrids. Both of these studies suggest that tumour suppressor genes play a dominant role in lung carcinogenesis and provide in-vitro model systems for isolating these genes by subtraction library and insertional mutagenesis techniques.
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PMID:Role of oncogenes and tumour suppressor genes in human lung carcinogenesis. 185 68

We have used 14 DNA probes, which detect 19 different restriction enzyme length polymorphisms, to search for heterozygosity on chromosome 3 in five cell lines isolated from patients with small cell lung carcinoma. The cell lines on karyotype analysis did not show the deletion in chromosome 3 characteristic of this disease. Our objective was to determine if allelic loss had occurred by some chromosomal mechanism other than deletion. Two of the cell lines are consistent with allelic loss having occurred by whole chromosome loss and reduplication. The third may have lost only the short arm due to i(3q) formation. The fourth cell line has an i(3q) chromosome, together with a translocation product involving the distal portion of the short arm of chromosome 3. Lack of evidence of heterozygosity for this distal portion of 3p suggests that a copy of the 3p homologue is involved in the translocation and therefore does not explain allelic loss of of the other homologue. The fifth, while also likely to have lost one chromosome homologue, has a submicroscopic deletion on all chromosome 3s, only detectable by RFLP analysis. Such homozygous deletions have recently proved useful in the isolation of tumour suppressor genes.
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PMID:A submicroscopic homozygous deletion at the D3S3 locus in a cell line isolated from a small cell lung carcinoma. 198 39

The results of conventional treatments for lung cancer remain poor and long-term survival rates have changed little over the last 10 years. In the same period of time there has been an explosion in the knowledge on the processes of cellular transformation, tumour progression, invasion and metastasis. The major categories of biological events implicated in non-small cell lung cancer include growth factor receptors expression (epidermal growth receptor, p185c-neu), autocrine growth factor production (transforming growth factor alpha), dominant oncogenes activation (ras genes) and deletion of tumour suppressor genes (p53 gene, retinoblastoma gene) and these are some of the abnormalities associated with specific histological types and with poor prognosis. Additional prognostic information can be obtained from the evaluation of the ploidy and proliferative activity of the tumours, carbohydrate antigens expression, presence of neuroendocrine differentiation and the evaluation of markers of the sequential steps involved in the process of tumour dissemination.
Lung Cancer 1995 Apr
PMID:Biological prognostic factors in non-small cell lung cancer. 755 21

The retinoblastoma (RB) tumour suppressor gene has been associated not only with retinoblastoma but also with several other tumours like osteosarcoma, small cell lung carcinoma and prostate and breast cancer. We have studied the incidence of RB gene alterations in 96 primary breast tumours using Southern blotting techniques. The outcome has been related with patient and tumour characteristics, oncogene amplifications, p53 mutations and prognosis. RB gene alterations were found to occur more frequently in estrogen receptor (ER)-positive than in ER-negative tumours and less frequently in tumours with oncogene amplification than in tumours without oncogene amplification of HER2/neu, c-myc or 11q13. RB gene alteration was observed in tumours both with and without a p53 gene mutation. Data on 87 patients (mean age, 59.6 years; median follow-up, 108 months) and RB gene alterations revealed a significant association between the frequency of RB gene alterations and node-negative patients (p < 0.01) or smaller (< 2 cm) tumours (p < 0.01), but no relation with age, differentiation grade or (relapse-free) survival. Patients with and without RB gene alterations showed the same relapse-free and overall survival.
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PMID:Association between RB-1 gene alterations and factors of favourable prognosis in human breast cancer, without effect on survival. 761 56

By successive screenings of cDNA libraries prepared from human tumours and from human foreskin keratinocytes, we have isolated overlapping cDNAs coding for a novel protein which we call Ron, with sequence characteristics of a receptor protein tyrosine kinase. Ron is a 1400 amino acid protein structurally similar to the 1408 amino acid product of the C-MET proto-oncogene, the receptor for hepatocyte growth factor and scatter factor. The two proteins have 63% overall sequence identity in their intracellular regions. We have localised the RON gene to human chromosome region 3p21, a region frequently deleted in small cell carcinoma of the lung and in renal cell carcinoma, and which is believed to harbour unidentified tumour suppressor genes. Interestingly, normal lung tissue contains transcripts of the RON gene.
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PMID:A novel putative receptor protein tyrosine kinase of the met family. 838 24

The retinoblastoma susceptibility gene (Rb) has been characterized as a tumour suppressor gene. Rb protein is involved in cell-cycle control, regulating gene transcription. The absence of Rb protein in inherited retinoblastoma has been proved to be the result of inactivation of both Rb alleles through mutation or deletion, according to the general model for suppressor genes. The frequent detection of Rb gene alterations in human tumours (retinoblastoma, osteosarcoma, bladder carcinoma, small-cell lung carcinoma) and the correlation with clinical outcome found in some tumours prompted us to study Rb gene expression in lymphoid tumours in an attempt to determine whether Rb gene expression is related to histological type and degree of aggressivity in human lymphomas. To establish normal levels of Rb protein, its expression was analysed in vitro on cytospin preparations from normal and pokeweed mitogen (PWM) or phytohaemagglutinin (PHA)-stimulated peripheral blood lymphocytes (PBLs), using a monoclonal antibody (PMG3-245). Rb protein expression in vivo was quantified using a computer analysis system (CAS) on frozen sections from reactive and neoplastic lymphoid tissue. As a control of tissue preservation, and to compare Rb expression and growth fraction, the tumours and cells were labelled simultaneously with the Ki67 monoclonal antibody. Normal and stimulated lymphocytes showed a gradual increase of Rb protein during progression of the cell cycle, with a peak in the M phase. G0-G1 cells had no detectable levels of Rb protein, suggesting that the Rb gene may act as a 'status quo' cellular growth fraction control mechanism. In reactive lymphoid tissue, Rb protein was mainly expressed in germinal centres (lymph nodes, tonsils) and cortical thymocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Retinoblastoma (Rb) gene product expression in lymphomas. Correlation with Ki67 growth fraction. 850 37

Accumulation of the tumour suppressor gene p53 product due to a gene mutation is frequently seen in human carcinomas, including lung carcinoma. Another indirect mechanism involving p53 in malignant growth relates to the E6 protein of the human papillomavirus (HPV), which is able to bind and degrade wild-type p53 protein, thus eliminating its tumour suppressor activities. Bronchiolo-alveolar carcinoma (BAC) is a rare type of lung carcinoma. The aim of our study was to examine the occurrence of p53 accumulation and the presence of HPV DNA in BAC. Sections of 22 BACs were immunohistochemically stained using a p53 antibody, CM-1. The presence of HPV DNA in BACs was verified by in situ hybridisation for HPV types 6, 11, 16, 18, 31 and 33 and confirmed by PCR. Thirty-six percent of the tumours showed abnormal p53 nuclear accumulation, and HPV DNA, revealed by in situ hybridisation, was found in 36%. Unexpectedly, only 13% of the type 1 BACs were positive for p53, whereas 45% of the type 2 BACs were positive. During a follow-up of 12-176 months, only 10% of the patients with BACs negative for both p53 and HPV died of the disease, compared with 42% of the patients with either p53 or HPV positivity. No inverse relationship between abnormal p53 protein accumulation and the presence of HPV DNA was found.
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PMID:p53 protein accumulation and the presence of human papillomavirus DNA in bronchiolo-alveolar carcinoma correlate with poor prognosis. 855 Feb 45

Certain oncogenes and tumour suppressor genes are known to modulate apoptosis. To investigate whether overexpressed bcl-2 and abnormally stabilized p53 are associated with reduced apoptosis in paraffin sections of non-small cell lung carcinoma, apoptotic, mitotic, and Ki-67 labelling indices were determined and correlated with bcl-2 and p53 immunoreactivity in 54 squamous cell carcinomas and 22 adenocarcinomas. Nineteen squamous cell carcinomas (35.2%) showed over-expression of bcl-2, but all 22 adenocarcinomas were bcl-2 negative. Thirty-seven squamous cell carcinomas (68.5%) and 13 adenocarcinomas (59.1%) showed p53 over-expression. Apoptotic tumour cells were identified among p53 positive and bcl-2 positive tumour cells. There was a significant linear correlation between apoptotic indices and mitotic indices. bcl-2 over-expression and p53 over-expression were not associated with attenuated apoptosis, or altered mitotic or Ki-67 labelling indices in either tumour type. Neither bcl-2 nor p53 was of prognostic significance. These results suggest that apoptosis in non-small cell lung carcinoma occurs independently, and is not modulated primarily by, bcl-2 or p53. It is likely that the effects on apoptosis of bcl-2 and p53 are countered by those of other oncogene products and/or additional factors that regulate apoptosis in vivo.
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PMID:Apoptosis occurs independently of bcl-2 and p53 over-expression in non-small cell lung carcinoma. 881 93

The H-rev107 tumour suppressor was isolated as a gene specifically expressed in rat fibroblasts resistant toward malignant transformation by the activated HRAS gene (Sers et al., 1997; Hajnal et al., 1994). Here we describe the human homologue of the rat H-rev107 gene. The predicted rat and human proteins are highly conserved exhibiting an overall amino acid identity of 83%. The H-REV107-1 gene is ubiquitously expressed with the exception of haematopoetic cells and tissues. In contrast, H-REV107-1 mRNA was found only in eight of 27 cell lines derived from mammary carcinoma, lung carcinoma, gastric carcinoma, kidney carcinoma, melanoma, neuroblastoma and other tumours. The H-REV107-1 protein was not detectable in any of these tumour cells. Loss of H-REV107-1 expression was not restricted to cultured human tumour cell lines, but also found in primary squamous cell carcinomas. Gross structural aberrations of the H-REV107-1 gene were absent in tumorigenic cell lines. Thus, the block to H-REV107-1 expression is achieved both at the level of transcription and translation. By fluorescence in situ hybridisation the human H-REV107-1 gene was localised to chromosome 11q11-12.
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PMID:Transcriptional and translational downregulation of H-REV107, a class II tumour suppressor gene located on human chromosome 11q11-12. 977 74


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