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)

It is widely believed that the cellular transcription factor DRTF1/E2F integrates cell cycle events with the transcription apparatus because during cell cycle progression in mammalian cells it interacts with molecules that are important regulators of cellular proliferation, such as the retinoblastoma tumour suppressor gene product (pRb), p107, cyclins and cyclin-dependent kinases. Thus, pRb, which negatively regulates early cell cycle progression and is frequently mutated in tumour cells, and the Rb-related protein p107, bind to and repress the transcriptional activity of DRTF1/E2F. Viral oncoproteins, such as adenovirus E1a and SV40 large T antigen, overcome such repression by sequestering pRb and p107 and in so doing are likely to activate genes regulated by DRTF1/E2F, such as cdc2, c-myc and DHFR. Two sequence-specific DNA binding proteins, E2F-1 and DP-1, which bind to the E2F site, contain a small region of similarity. The functional relationship between them has, however, been unclear. We report here that DP-1 and E2F-1 exist in a DNA binding complex in vivo and that they bind efficiently and preferentially as a heterodimer to the E2F site. Moreover, studies in yeast and Drosophila cells indicate that DP-1 and E2F-1 interact synergistically in E2F site-dependent transcriptional activation.
 ...
PMID:Functional synergy between DP-1 and E2F-1 in the cell cycle-regulating transcription factor DRTF1/E2F. 822 41

Proto-oncogenes, growth factors/receptors, and tumour suppressor genes were analysed in malignant metastatic insulinomas. Normal pancreas showed only a moderate immunoreaction for c-myc proto-oncogene and a strong reaction for insulin. Benign insulinomas were slightly or moderately positive for transforming growth factor alpha (TGF alpha), weakly positive for epidermal growth factor receptor (EGF-R), and strongly positive for c-myc and insulin. In malignant insulinomas, besides a strong immunoreaction for c-myc and TGF alpha, activation of c-K-ras and overexpression of p53 protein were found. Insulin reaction was moderate or strong. Three out of six malignant insulinomas displayed a c-K-ras point mutation at codon 12. All mutations were guanine to cytosine transversion, resulting in amino acid substitution, glycine to arginine. Mutations were present in metastatic insulinomas only. Patients with mutated c-K-ras oncogene had overexpression of p53 protein as well as c-myc and TGF alpha overexpression. Our results support the view that malignant progression is a consequence of more than one genetic lesion and suggest that activation of myc, TGF alpha an ras genes plays a role in a multistep process of tumour progression, perhaps serving as an initiating event.
 ...
PMID:Multiple genetic alterations in malignant metastatic insulinomas. 856 94

The expression of oncogenes c-myc, c-jun and c-raf and tumour suppressor gene p53 was assessed by northern blot analysis of 42 tumours and p53 protein expression by immunohistochemistry on paraffin-embedded sections from 36 specimens of squamous cell carcinoma of the head and neck (SCCHN) obtained before therapy. Of the 42 tumours, 89, 100 and 100% expressed c-myc, c-jun and c-raf oncogenes, respectively. These oncogene expressions did not correlate with sex, age or clinical stage of the disease. However, an association was found between low c-myc expression (P = 0.0001) and high c-jun expression (P = 0.0001) and absence of tumoral response to neoadjuvant chemotherapy. On the other hand, c-raf overexpression was observed in patients resistant to radiation therapy (P = 0.0494). Forty-two per cent of the tumours showed p53 protein overexpression, which did not correlate with any clinical parameter. This p53 protein overexpression was associated with high p53 mRNA levels (REL) (P = 0.0223). A correlation was found between increased c-myc RNA expression and lack of p53 protein expression (P = 0.0407). In addition, a lack of p53 protein expression was indicative of tumour relapse (P = 0.05). None of these biological parameters were associated with disease-free survival (Cox-Mantel test). In conclusion, the overexpression of c-myc, c-jun and c-raf may be independently associated to tumoral response to chemotherapy or radiotherapy, or to tumour relapse, but fail to predict long-term survival.
 ...
PMID:Differential c-myc, c-jun, c-raf and p53 expression in squamous cell carcinoma of the head and neck: implication in drug and radioresistance. 874 69

Improved success in the management of colorectal cancer requires a better understanding of its development and biological behaviour. The key for this is molecular genetics. Gene changes parallel the multi-step changes in the adenoma-carcinoma sequence. Cancer results from a variable combination of defects in oncogenes, tumour suppressor, mutator and apoptotic genes. These changes are similar whether they occur in inherited disorders like adenomatous polyposis coli (APC) and hereditary non-polyposis colorectal cancer (HNPCC) or acquired cancer in the elderly. In Singapore, the c-myc and c-Ki-ras proto-oncogenes are found to be activated in 70% and 29% of tumours respectively. Allelic loss of chromosome 5q and 17p occurs in 25% and 70% of tumours respectively, while point mutation of the p53 tumour suppressor gene occurs in 50% of colorectal cancers. Both the frequency and the nature of the lesion occurring are compatible to the changes detected in Caucasian patients, suggesting common aetiological factors. The biological behaviour of colorectal adenocarcinomas is determined by the nature of defects or mutations in key genes such as the p53 tumour suppressor gene. Lymphatic spread is associated with the presence of point mutations and haematogenous spread is associated with loss of heterozygosity of p53. Survival is worse when conserved regions of the gene are mutated compared with those outside, and worst when codon 175 is mutated. Sensitivity to radiotherapy and chemotherapy is also determined by p53 mutation which controls apoptosis. Prognosis could now be individualised and with the prospect of gene therapy, molecular genetics will have a major impact on the management of colorectal cancer.
 ...
PMID:Molecular changes of colorectal cancer in Singapore. 877 42

1. Overexpression of the c-myc oncogene is associated with a variety of both human and experimental tumours, and cooperation of other oncogenes and growth factors with the myc family are critical in the evolution of the malignant phenotype. 2. Double transgenic mice bearing fusion genes consisting of mouse albumin enhancer/promoter-mouse c-myc cDNA and mouse metallothionein 1 promoter-human transforming growth factor (TGF-alpha) cDNA were generated to investigate the interaction of these genes in hepatic oncogenesis and to provide a general paradigm for characterizing the interaction of nuclear oncogenes and growth factors in tumourigenesis. 3. Coexpression of c-myc and TGF-alpha as transgenes in the mouse liver resulted in a tremendous acceleration of neoplastic development in this organ as compared to expression of either of these transgenes alone. The two distinct cellular reactions that occurred in the liver of the double transgenic mice prior to the appearance of liver tumours were dysplastic and apoptotic changes in the existing hepatocytes followed by emergence of multiple focal lesions composed of both hyperplastic and dysplastic cell populations. 4. These observations suggest that the interaction of c-myc and TGF-alpha, during development of hepatic neoplasia contributes to the selection and expansion of the preneoplastic cell populations which consequently increases the probability of malignant conversion. 5. We have now extended these studied and examined the interaction of hepatocyte growth factor (HGF) with c-myc during hepatocarcinogenesis in the transgenic mouse model. While sustained overexpression of c-myc in the liver leads to cancer, coexpression of HGF and c-myc in the liver delayed the appearance of preneoplastic lesions and prevented malignant conversion. Similarly, tumour promotion by phenobarbitone was completely inhibited in the c-myc/HGF double transgenic mice whereas phenobarbitone was an effective tumour promoter in the c-myc single transgenic mice. 6. The results indicate that HGF may function as a tumour suppressor during early stages of liver carcinogenesis, and suggest the possibility of therapeutic application for this cytokine. Furthermore, we show for the first time that interaction of c-myc with HGF or TGF-alpha results in profoundly different outcomes of the neoplastic process in the liver.
 ...
PMID:Transgenic mouse models in carcinogenesis: interaction of c-myc with transforming growth factor alpha and hepatocyte growth factor in hepatocarcinogenesis. 880 43

A characteristic feature of colorectal cancer genesis is its stepwise progression, which offers unique possibilities for studying its development. There are two principal kinds of mutation leading to uncontrolled cell proliferation and cancer. The first renders a stimulatory gene hyperactive--generation of an oncogene--and the second is the inactivation of a tumour suppressor gene. Current knowledge suggest that the change from normal mucosa to a small adenoma may be mediated by mutations of the APC gene and MCC gene on chromosome 5, by chromosome 5 deletion, by c-myc activation, and by DNA hypomethylation. The development to a large adenoma may be caused by Ki-ras mutation and further change to a dysplastic adenoma by deletion of the DCC gene on chromosome 18. The ability to become an invasive carcinoma may then be mediated by p53 mutations and deletion of chromosome 17p. Identification of genetic markers for metastatic disease is under progress.
 ...
PMID:Genetic aspects of colorectal cancer: the surgeon's view. 889 51

Hodgkin's disease (HD) is characterized by the presence of the typical, clonal malignant Hodgkin and Reed-Sternberg (H-RS) cells in a hyperplastic background of normal reactive lymphocytes, plasma cells, histiocytes, neutrophils, eosinophils and stromal cells. The neoplastic nature of HD is based on aggressive clinical progression, presence of the proliferating and atypical H-RS cells, aneuploidy and cellular clonality. Immunophenotypical studies have demonstrated frequent expression of lymphoid "activation markers' including CD15, CD25, CD30, CD40, CD54, CD70, CD71, CD80, CD86 and MHC class II and less frequent expression of T- or B-cell-associated antigens by the neoplastic H-RS cells. The clonality of H-RS cells is demonstrated by clonal EBV integration, clonal cytogenetic abnormalities including p53 mutations and clonal immunoglobulin rearrangements in some HD cases. There is involvement of diverse molecules with oncogenic potential, including presence of viruses (Epstein-Barr virus and human herpes virus-6) and/or oncogenes/tumour suppressor genes (bcl-2/bcl-x, p53/MDM-2, c-myc, c-fms, N-ras, lck). The histopathological presentation and characteristic clinical features of HD correlate with an unbalanced production of multiple cytokines and define HD as a tumour of cytokine-producing cells. The proportion of malignant H-RS cells to reactive cellular components and fibrosis is dependent on the production of particular cytokines and allows subtyping of HD cases. The combined use of immunohistochemical, biochemical and molecular techniques has thus allowed recognition that HD represents more than one clinico-pathological entity with different types of H-RS cells. The defined mechanism for the biological nature, origin and oncogenesis of H-RS cells remains not fully understood, but is susceptible to further analysis using modern technology.
 ...
PMID:Pathophysiology of Hodgkin's disease: functional and molecular aspects. 892 38

The dysregulation of specific oncogenes due to either mutation or activation has previously been reported in a small number of patients with myeloma but the extent of oncogene dysregulation during the course of the disease is not known. The oncoprotein phenotype of plasma cells in 146 bone marrow samples from 81 patients with multiple myeloma was determined by dual colour flow cytometry using a predetermined panel of 8 monoclonal antibodies. High intensity CD38 expression was used to distinguish the plasma cell population and the cells were permeabilised to detect intracellular antigen expression. In situ hybridization using biotinylated cDNA probes for c-myc and bcl-2 was used to determine mRNA expression and to validate the flow cytometric assay. The normal range of expression for each of 6 oncoproteins (c-myc, c-fos, c-neu, bcl-2, p-ras, p53 mutant) and 2 tumour suppressor gene products (p53 wild and Rb) was determined in plasma cells from 33 normal bone marrows. Disease progression was associated with the concurrent abnormal expression of at least one oncogene and one tumour suppressor gene where as stable disease was associated with a normal expression of at least one or both (chi2 = 34.1; p < 0.001). At diagnosis there was a correlation between serum beta2 microglobulin and the concurrent overexpression of both an oncoprotein and a tumour suppressor gene product. Longitudinal studies of 33 different patients over 4 years, suggests that the progressive evolution of myeloma is a multistep process of genomic instability producing ongoing alterations in the expression of both oncogenes and tumour suppressor genes.
 ...
PMID:Disease progression in patients with multiple myeloma is associated with a concurrent alteration in the expression of both oncogenes and tumour suppressor genes and can be monitored by the oncoprotein phenotype. 925 Aug 26

Within past few years, the investigation of molecular genetic markers has had an increasing influence on clinical decisions about initial treatment and follow-up. This review presents data concerning the most studied and interesting molecular markers in ovarian cancer. p53 tumour suppressor gene, Bcl-2 oncogene, K-ras oncogene, c-erb2 proto oncogene, c-myc oncogene are examples of currently used molecular genetic markers. Some of these markers might be useful adjuncts for monitoring response to therapy, including early detection of tumour reactivation to allow curative therapy and rapid detection of treatment failure. The study of these markers may also lead to a better understanding of the biological characteristics of ovarian cancer. The information derived from studies of these markers also represents the most promising avenue towards new treatment strategies.
 ...
PMID:[Molecular markers in ovarian cancer]. 959 89

Tumour suppressor genes may have a role in the control of trophoblast cell population expansion as trophoblast invasion occurs. To investigate this hypothesis, the location of tumour suppressor gene and proto-oncogene products were studied at various stages of trophoblast differentiation and invasion. Trophoblast and decidua were obtained from eight women having a therapeutic termination of pregnancy. Immunohistochemistry was used to localize the products of c-myc, c-erB-2, RB, BCL-2, P21, and P53 genes and anti-cytokeratin was used to identify fetal cells amongst the maternal decidual cells. The most differentiated and furthest invading trophoblast cell type, the multinucleated trophoblast, expressed a combination of genes which may indicate a high apoptotic rate. The other fully differentiated trophoblast, the syncytiotrophoblast, expressed BCL-2 suggesting protection from apoptosis. The co-occurrence of proto-oncogenes and the products of tumour suppressor genes in first trimester trophoblast suggests an important role not only in negative regulation of cellular invasion but also in population expansion through the presence of oncogenes and anti-apoptotic proteins.
 ...
PMID:Oncogene and tumour suppressor gene products during trophoblast differentiation in the first trimester. 966 34


<< Previous 1 2 3 4 5 Next >>