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)

Inactivation of the retinoblastoma susceptibility gene (RB-1) has been associated with the aetiology of many types of human cancers, leading to the classification of RB-1 as an anti-oncogene or tumour suppressor gene. Given that the protein product of RB-1 (Rb) has a nuclear localization and DNA-binding activity in vitro, it is possible that Rb regulates transcription of certain genes. The promoter of the c-fos gene might be a target for regulation by Rb, because both v-fos and RB-1 are associated with the induction of osteosarcomas in mice and humans, respectively. Also, fos expression is thought to be required for quiescent cells to enter the cell cycle, making the fos promoter an attractive target for suppressors of cell growth. Here we report that Rb can repress c-fos expression and AP-1 transcriptional activity in both serum-induced and cycling 3T3 cells. We have mapped a cis-acting element in the human c-fos promoter that can confer repression by Rb to a heterologous promoter. We have the termed the cis-acting sequence regulated by Rb the retinoblastoma control element.
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PMID:Negative regulation of human c-fos expression by the retinoblastoma gene product. 211 57

The aim of the present study was to identify genes whose expression and/or organisation are altered in the diseased breast, as compared to the normal breast. Alteration of one or more genes examined has been found to occur in over 60% of breast tumour samples. Changes to three cellular proto-oncogenes are frequent, and amplification of two of these genes correlates with poor short-term prognosis. Deletion of RB-1, a tumour suppressor gene, has been detected and although these deletions do not correlate with poor prognosis, they occur more commonly in advanced tumours. A loss of sequences encoding the progesterone receptors has also been found to be frequent.
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PMID:Oncogene organisation and expression: prediction in breast cancer. 261 10

Loss of function of one or both of the two tumour suppressor genes p53 and RB-1 has been recognised as an important step in the development of a variety of human neoplasias for some time. By virtue of the ability to manipulate the genome of murine embryonic stem cells in culture, it has become possible to generate strains of mice which bear inactivations of the murine counterparts of these genes. This article attempts to bring together some of the many results obtained from these murine strains which are shedding light both on the normal role played by both of these genes and the consequences of their dysfunction. Surprisingly neither gene product is revealed to have an indispensable role at the level of the single cell. Hence, even though the Rb-1 gene product clearly has an important role in cell cycle regulation animals constitutively deficient in this gene develop relatively normally for the first 10 days of embryogenesis. It is only at and beyond this stage of development that a requirement for Rb-1 becomes clear, in the regulation of certain cell populations through control of both proliferation and apoptosis. That loss of function of Rb-1 is associated with tumorigenesis is confirmed by the development of tumours of the pituitary gland within heterozygotes. The retinas of these animals, the target organ for tumorigenesis in human RB-1 heterozygotes, remain unaffected. The majority of mice homozygous for an inactivating p53 mutation survive to birth, but then rapidly succumb to tumorigenesis. Heterozygotes also develop tumours, but with a delayed time course and altered spectrum. Analysis of several tissue types from the mutant animals has shown p53 to be crucial for the normal induction of apoptosis following DNA damage, and it is thought that failure of this process is a key predisposing step towards tumorigenesis within the mutant animals. Finally, studies on these and other transgenic strains have revealed interactions between pathways governed by these two genes. For example, the fate of Rb-1 deficient cells has been shown, in some tissues at least, to be dependent upon the functional status of p53.
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PMID:Murine models of neoplasia: functional analysis of the tumour suppressor genes Rb-1 and p53. 755 30

We have investigated the RB-1 tumour suppressor genes in a series of 20 non-Hodgkin's lymphomas (NHL). Polymerase chain reaction (PCR) amplification of polymorphic alleles indicated that there was evidence of allelic imbalance around 13q14, the site of the RB-1 gene, in at least 5 NHL. Immunohistochemical analysis of the RB-1 protein demonstrated wide variations in the percentage of cells exhibiting positive staining, but these usually correlated with differences in the proliferation index as indicated by staining of Ki67. Only 3/35 NHL exhibited significantly fewer cells expressing RB-1 protein than expressed Ki167. A comprehensive analysis of the mutation status of RB-1 in 20 NHL was carried out using PCR based strategies involving single strand conformational polymorphism (SSCP) gels. Most of the protein coding region was studied by analysing cDNA derived from its mRNA and the remaining 5'-end of the coding region investigated by analysing exon I of the gene. We also examined the promoter region of the gene. In none of the 20 NHL investigated were we able to identify a mutation: the only abnormal migrating fragment observed proved to be a polymorphism in exon I of the gene in 5 NHL. In one other case we detected instability at an intron repeat sequence, which had occurred during progression of the disease, but again no mutation of the protein coding region was found. The low levels of RB-1 protein expression that we had observed in a few of our NHL therefore did not appear to be due to mutation of the gene. These data suggest that mutation of RB-1 is not a common event in the evolution of NHL, but that there may be another, as yet unidentified, tumour suppressor gene near the RB-1 locus which is associated with NHL.
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PMID:Investigation of the RB-1 tumour suppressor gene in a United Kingdom series of non-Hodgkin's lymphomas. 903 Nov 17

To study genetic changes associated with the development of breast cancer and the extent of its hereditary predisposition, paraffin-embedded tissue samples were obtained from monozygotic twin pairs concordant for breast cancer through the linked Swedish Twin and Cancer Registries. DNA samples extracted from the matched tumour and normal tissues of nine twin pairs were analysed for allelic imbalance using a series of microsatellite markers on chromosomes 13 and 17, containing loci with known tumour suppressor genes. Multiple losses of constitutional heterozygosity (LOH), consistent with a loss of large genomic region, the whole chromosome or chromosome arm, was found in at least three pairs of twins. One double mitotic crossover was identified in one tumour sample in a pair concordant for LOH at multiple loci on both chromosomes. Recombination breakpoints were mapped to regions delineated by D13S218 and D13S263, and D13S155 and D13S279, respectively. In general, no genetic effect of losing the same allele within a twin pair was found. However, for one marker at chromosome 13 (D13S328, between the BRCA2 and the RB-1 loci) and two markers on chromosome 17 (D17S786, distal to the p53 locus, and D17S855, an intragenic BRCA1 marker) the proportion of twin pairs with the same LOH was significantly higher than expected. These regions may reflect hereditary genomic changes in our sample set. In addition, tumour DNA samples from a subset of 12 twin pairs were analysed for BRCA1 and BRCA2 mutations using exon-by-exon single-strand conformation polymorphism analysis. Two unclassified BRCA2 variants, with a putative pathogenic effect, were identified, but no pathogenic alterations were found in the BRCA1 gene.
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PMID:Allelic imbalance on chromosomes 13 and 17 and mutation analysis of BRCA1 and BRCA2 genes in monozygotic twins concordant for breast cancer. 1115 37

Deletions of 13q14.3 are well known in several malignancies and are thought to be associated with tumour suppressor function. The RB-1 gene is a tumour suppressor gene, but other loci including D13S319 and D13S25 telomeric to this within 13q14.3 are deleted in B-cell chronic lymphocytic leukaemia (B-CLL), multiple myeloma and non-Hodgkin's lymphoma, with varying clinical significance. The fluorescence in situ hybridization screening of 22 patients with T-prolymphocytic leukaemia (T-PLL) for deletions of 13q14.3 revealed loss of D13S25 in 17 cases (mean 40% range 13-98%), with 11 patients having at least a 20% deletion. Mapping the deletions for the RB-1, D13S319,and D13S25 loci revealed D13S25 as the most frequently deleted marker. However, patients with only the D13S25 deletion had low percentages of cells with the deletion (12-13%), suggesting that loss of D13S25 on its own may not provide sufficient growth advantage. The use of the YAC 954c12, which maps immediately adjacent to D13S25, defined the telomeric border of the deletion in some of the cases. Inv(14)(q11q32) and t(14;14)(q11;q32) are characteristic of T-PLL, but are also observed in premalignant T-cell clones in patients with ataxia telangiectasia. Transition to overt leukaemia may result from loss of suppressor function. Thus, 13q14.3 deletions could contribute to the development of overt leukaemia in T-PLL, but the involvement of more than one gene in the region cannot be excluded.
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PMID:Deletions of D13S25, D13S319 and RB-1 mapping to 13q14.3 in T-cell prolymphocytic leukaemia. 1152 51

Hepatocellular carcinoma (HCC) is one of the most frequent-occurring malignant tumours worldwide, but molecular changes of tumour DNA, with the exception of viral integrations and p53 mutations, are poorly understood. In order to search for common macro-imbalances of genomic tumour DNA, 21 HCCs and 3 HCC-cell lines were characterized by comparative genomic hybridization (CGH), subsequent database analyses and in selected cases by fluorescence in situ hybridization (FISH). Chromosomal subregions of 1q, 8q, 17q and 20q showed frequent gains of genomic material, while losses were most prevalent in subregions of 4q, 6q, 13q and 16q. Deleted regions encompass tumour suppressor genes, like RB-1 and the cadherin gene cluster, some of them previously identified as potential target genes in HCC development. Several potential growth- or transformation-promoting genes located in chromosomal subregions showed frequent gains of genomic material. The present study provides a basis for further genomic and expression analyses in HCCs and in addition suggests chromosome 4q to carry a so far unidentified tumour suppressor gene relevant for HCC development.
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PMID:Frequent genomic imbalances suggest commonly altered tumour genes in human hepatocarcinogenesis. 1153 Dec 55