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 a study of DNAs from 100 breast cancer patients and 100 controls, there were no differences in the frequencies of common or rare alleles at the Harvey ras (c-Ha-ras) locus on chromosome 11. However, one Ha-ras allele was deleted from the tumour DNA in 14 of 65 informative patients. Loss of a Ha-ras allele correlates with paucity of oestrogen receptor protein and with increased tumour size at presentation, but is not associated with microscopic evidence of lymph node invasion. The findings on Ha-ras and other informative loci are consistent with the possibility that a tumour suppressor gene involved in the early stages of breast cancer is located on the short arm of chromosome 11.
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PMID:Partial deletion of chromosome 11p in breast cancer correlates with size of primary tumour and oestrogen receptor level. 306 95

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.
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PMID:Biological prognostic factors in non-small cell lung cancer. 755 21

The expression of 6 different oncoproteins and 2 tumour suppressor gene products in the plasma cells of 63 bone marrow samples was used to determine a profile of the oncogenic phenotype of patients with multiple myeloma. Dual label flow cytometry after periodatelysine paraformaldehyde fixation was used to detect cell surface phenotype and intracellular protein expression simultaneously. The normal range for both the incidence and intensity of expression was determined for each protein by analysing plasma cells (high CD38 intensity) in 22 normal bone marrow samples. The percentage of myeloma patients with a greater than normal incidence of plasma cells expressing these proteins was 53% for c-myc, 28% for Rb, 28% for bcl-2, 27% for c-fos, 24% for p53 wild, 22% for p53 mutant, 13% for c-neu and 13% for pan-ras. When a panel of 8 antibodies was used, 82% of the samples (n = 28) had an increased incidence of expression by at least one oncoprotein or tumour suppressor gene product. The 5 patients with a normal incidence of expression of all 8 proteins were in plateau stage and 4 had not received chemotherapy for more than 12 months. The number of patients with an increased incidence of expression by 2 or more oncoproteins was significantly greater (X2 = 9.0; p < 0.005) in progressive disease (55%) than in stable disease (14%) but there was no specific phenotype pattern associated with progressive disease. All 6 oncoproteins and both tumour suppressor gene products had a greater incidence and intensity of expression in progressive than in stable disease. The expression of c-myc oncoprotein correlated with c-myc mRNA expression in the same samples (n = 10) but c-myc did not correlate with either the plasma cell labelling index (r = -0.15) nor serum thymidine kinase (r = 0.10). Our results suggest that there is a heterogeneous, non-systematic but almost universal presence of activated oncogenes and tumour suppressor genes in the plasma cells of patients with multiple myeloma and that disease progression is associated with the accumulation of a variety of secondary genetic changes which confer increased malignant behaviour.
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PMID:The oncoprotein phenotype of plasma cells from patients with multiple myeloma. 769 21

The cellular transcription factor DRTF1/E2F is implicated in the control of cellular proliferation due to its interaction with key regulators of cell cycle progression, such as the retinoblastoma tumour suppressor gene product, cyclins and cyclin-dependent kinases. DRTF1/E2F is a heterodimeric DNA binding activity which arises when a member of two distinct families of proteins, DP and E2F, interact as DP/E2F heterodimers, for example, DP-1 and E2F-1. In DRTF1/E2F the activity of DP-1 is under cell cycle control, possibly by phosphorylation, and in many types of cells it is a frequent, if not general DNA binding component of DRTF1/E2F. The expression of other DP proteins, such as DP-2, is tissue-restricted. Here, we show that DP-1 and DP-2 are integrated with another growth regulating pathway which involves signal transduction emanating from activated Ras protein. Thus, activated Ha-ras can co-operate with DP-1 or DP-2 in the transformation of rat embryo fibroblasts, establishing for the first time that DP proteins are endowed with proto-oncogenic activity. Moreover, an analysis of a dominant-negative and mutant DP-1 proteins suggests that the primary target through which DP-1 mediates its oncogenic activity is unlikely to be due to the regulation of E2F site-transcription, suggesting an E2F-independent effector function for DP-1. These results therefore establish DP genes as proto-oncogenes and thus argue that deregulating the normal control of DP protein activity will be important in promoting aberrant cellular proliferation.
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PMID:Proto-oncogenic properties of the DP family of proteins. 773 7

Amplification in rodent cells usually involves bridge-breakage-fusion (BBF) cycles initiated either by end-to-end fusion of sister chromatids, or by chromosome breakage. In contrast, in human cells, resistance to the antimetabolite N-(phosphonacetyl)-L-aspartate (PALA) can be mediated by several different mechanisms that lead to overexpression of the target enzyme carbamyl-P synthetase, aspartate transcarbamylase, dihydro-orotase (CAD). Mechanisms involving BBF cycles account for only a minority of CAD amplification events in the human fibrosarcoma cell line HT 1080. Here, formation of a 2p isochromosome and overexpression of CAD by other types of amplification events (and even without amplification) are much more prevalent. Broken DNA is recognized by mammalian cells with intact damage-recognition pathways, as a signal to arrest or to die. Loss of these pathways by, for example, loss of p53 or pRb tumour suppressor function, or by increased expression of ras and myc oncogenes, causes non-permissive rat and human cells to become permissive both for amplification and for other manifestations of DNA damage. In cells that are already permissive, amplification can be stimulated by overexpressing oncogenes such as c-myc or ras, or by damaging DNA in a variety of ways. To supplement genetic analysis of amplification in mammalian cells, an amplification selection has been established in Schizosaccharomyces pombe. Selection with LiCl yields cells with amplified sod2 genes in structures related to those observed in mammalian cells. The effect on amplification in S. pombe can now be tested for any mutation in a gene involved in repair of damaged DNA or in normal cellular responses to DNA damage.
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PMID:Regulation and mechanisms of gene amplification. 774 53

Growth factors, such as insulin, EGF, PDGF, are indispensable elements of the regulation of cell proliferation. In the last years signal transduction pathways of many growth factors have been elucidated. p21 ras, a proto-oncogene product, plays a central role in growth signalling. The medical importance of the investigation of Ras proteins comes from the fact that mutant forms of Ras genes were found in a number of human tumours. The review summarizes the signal transduction pathways of growth factors, with special respect to the connection of protooncogenes, tumour suppressor genes and cancer research.
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PMID:[Oncogenes and tumor suppressor genes in the signal transduction pathways of growth factors]. 782 56

The series of genetic changes leading to malignancy in colorectal cancer is well reported. This includes mutational activation of the proto-oncogene Ki-ras and mutation/deletion of the p53 tumour suppressor gene. The frequency of these mutations was investigated in a panel of 52 colorectal cancer patients using a combination of immunocytochemistry and non-radioactive, digoxigenin-labelled in situ hybridisation. Sixty two per cent (32 of 52) of the study population were positive for p53 overexpression and 36% (19 of 52) positive for Ki-ras mutation. Twenty seven per cent (14 of 52) of the patients expressed both mutations. Mutation of either the p53 or the Ki-ras gene did not correlate with Dukes's stage, tumour differentiation or 5 year survival rate of the patients. Most of the rectal carcinoma specimens (11 of 15) showed p53 over-expression but the significance of this was not supported statistically. Thus detection of molecular changes is becoming more amenable to incorporation into routine histological carcinoma assessment because of the advent of non-radioactive labelling in in situ hybridisation and antibodies suitable for paraffin wax embedded specimens. The significance of these mutations in disease prognosis, however, remains questionable.
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PMID:Mutations of Ki-ras and p53 genes in colorectal cancer and their prognostic significance. 782 87

The observation that oncogenes are frequently activated in human tumours raises the question of whether these genes are involved in chemical carcinogenesis. H-ras activation is probably an initiating event in mouse skin and rat mammary gland systems. The H-ras oncogene is also important in mouse liver tumours; in mouse lung the K-ras gene is commonly activated. In both, the mutations observed are usually those predicted from the adduct-forming properties of the carcinogen. Among non-ras oncogenes, only raf and neu have been detected in experimental tumours. Tumour suppressor genes are frequently inactivated in human tumours. Searches for such phenomena in animal tumours have generally had disappointing results. p53 and Rb gene alterations are rarely observed in chemically-induced tumours. The reason may be that unknown tumour suppressor genes are involved in animal tumour development. Several novel genes have been identified using animal tumour susceptibility models. Thus, ras genes are important in chemical carcinogenesis, but as the methodology for studying other genes improves, their roles will be seen in perspective.
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PMID:Molecular aspects of chemical carcinogenesis: the roles of oncogenes and tumour suppressor genes. 790 Jan 59

An immortal cell line was established by transfecting a myc oncogene into rat embryo cells (REC:myc). This cell line was diploid, contact inhibited and grew well in culture. Exposure to a single 200 cGy dose of 6 MeV alpha-particles transformed these cells with a frequency of focus formation of approximately 3.6 x 10(-4) compared with a transformation frequency of < 7.8 x 10(-6) for primary cultures of REC. Isolates of alpha-particle-induced REC:myc (REC:myc:alpha) foci displayed anchorage-independent growth in soft agar and were tumourigenic in nude mice. Molecular studies demonstrated no alteration of gene structure or expression of the transfected or of the endogenous c-myc genes. Similarly, there was no alteration of the structure of Ha-ras, Ki-ras, or N-ras. The expression of Ha-ras, Ki-ras, N-ras and raf was not altered significantly. Assay for dominant oncogenes via DNA-mediated gene transfer into NIH3T3 cells was positive for nine of 13 REC:myc:alpha transformants. All NIH3T3 isolates contained bands hybridizing to rat repetitive DNA. NIH3T3 transformants from a tertiary round of transfection were analysed by Southern blot analysis for the presence of Ki-ras, N-ras, raf, trk, abl, fms, src, mos, fos, sis, fps, erbA, erbB or neu oncogenes of REC origin, and none were detected. Tertiary NIH3T3 transformants from three REC:myc:alpha transformants contained bands corresponding to Ha-ras but no point mutations were identified at the known hotspots of exons 1 or 2 of the donor REC:myc:alpha transformants. The inactivation of the tumour suppressor genes Rb, and p53, and the anti-metastasis gene, nm23, was evaluated by Southern and Northern hybridization analysis. Southern blots demonstrated that at least one allele of Rb, p53 and nm23 was present and no large scale structural changes were detected. No expression of Rb or p53 was detected in REC:myc or the alpha-particle-induced REC:myc transformants. The expression of nm23 was not altered in the transformed cell lines. While the analysis of the role of tumour suppressor gene inactivation in radiation-induced cell transformation is only in the initial stages, the results of DNA-mediated gene transfer into NIH3T3 cells suggest that unidentified dominant oncogenes are associated with alpha-particle-induced transformation in vitro.
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PMID:Molecular analysis of rat embryo cell transformants induced by alpha-particles. 790 39

Carcinogenesis is a multi-step process including aberrant expression of two interacting classes of genes--oncogenes and tumour suppressor genes. With recent technological advances, it is feasible to identify the various molecular lesions underlying the different stages of neoplasia. Squamous cell carcinomas of the head and neck, although representing 2-4% of the malignancies in the West, comprise a large fraction (40%) of total cancers in India, posing a major health problem. Further, epidemiological and experimental evidence unequivocally confirms a causal association between tobacco chewing habit, highly prevalent in India, and oral cancers. Thus, the oral cancers offer an excellent in vivo system for the study of the environmental tobacco-carcinogen induced molecular alterations in the malignancy, and associated premalignant lesions such as leukoplakia. With a view to elucidating the molecular lesions involving oncogenes in oral carcinogenesis, we have investigated myc/ras/EGF-R activation by amplification, point mutation, gene rearrangement and allelic losses. Further, a functionally activated potent transforming gene was detected in a NIH3T3 transfection/tumorigenicity assay, unrelated to myc/ras/EGF-R. Studies on the involvement of p53 gene in oral cancer, indicates p53 allelic loss as an event observed in leukoplakia and tumour tissues. Advanced oral cancer stages demonstrate cumulative molecular aberrations, with greater than 95% samples showing oncogene involvement, thus indicating a multi-step process of oral carcinogenesis. The review presents a comparative picture of the oral malignancies seen in Western countries and India, significance of molecular lesions and future perspectives of oncogenes and tumour suppressor gene involvement in oral cancer.
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PMID:Molecular lesions in human oral cancer: the Indian scene. 791 88


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