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)

The c-met proto-oncogene encodes the receptor to hepatocyte growth factor-scatter factor (HGF-SF), a mesenchyme-derived cytokine with cell-dissociating, invasion, and angiogenic properties. The expression of c-met in breast cancer is the subject of controversy; 111 primary breast cancers were examined for LOH of c-met by Southern blot electrophoresis. c-met expression was measured in a further 40 patients with breast cancer and in 8 patients with benign breast disease by flow cytometry. LOH of c-met was detected in only 4% of informative breast cancers. Expression of c-met was significantly greater in patients with breast cancer than in those with benign breast disease (P < 0.01, Mann-Whitney). There was no correlation however between increased c-met expression and clinicopathological prognostic variables. These results do not support the role of c-met as a tumour suppressor gene in breast cancer but suggest increased receptor expression in malignant breast disease. The significance of this increased expression in breast cancer is the subject of further investigation.
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PMID:Expression and loss of heterozygosity of c-met proto-oncogene in primary breast cancer. 756 88

Active unspecific immunotherapy in an adjuvant or palliative setting has been shown to enhance survival in melanoma patients, and gene therapy now offers new perspectives for active specific immunotherapy. Gene therapy includes the transfer of genetic material performed by either viral or non-viral methods and in vivo or ex vivo. For melanoma the following approaches are suggested: vaccination with tumour-specific, HLA-associated antigens using peptides or 'naked DNA', vaccination with melanoma cells transfected with cytokine genes or B7, adoptive immunotherapy with specific T-lymphocytes or transfected tumour-infiltrating lymphocytes, or transfection of tumour cells with a tumour suppressor gene whose dysfunction plays a crucial role in melanoma.
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PMID:[Strategies for gene therapy of melanoma]. 760 92

In multiple myeloma the duration of plateau is an important clinical and biological determinant of quality of life and survival. During plateau phase, the tumour is in an indolent state, as manifested by a low labelling index of plasma cells and other proliferative markers, e.g. the thymidine kinase level. The mechanism by which plasma cells escape from this indolent phase to a more aggressive phase of this disease is unknown, but a number of possible mechanisms have been postulated. These include loss of immunoregulation, clonal evolution, cytokine dysfunction and oncogene activation or tumour suppressor gene dysfunction. As current chemotherapy protocols do not appear to be able to eradicate the malignant clone, understanding the nature of the indolent phase of the malignant clone and the reasons for its escape from this phase are very important and may provide new options for disease control.
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PMID:Mechanisms of the escape phase of myeloma. 820 6

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.
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PMID:Transgenic mouse models in carcinogenesis: interaction of c-myc with transforming growth factor alpha and hepatocyte growth factor in hepatocarcinogenesis. 880 43

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.
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PMID:Pathophysiology of Hodgkin's disease: functional and molecular aspects. 892 38

The Smad4/DPC4 tumour suppressor is inactivated in nearly half of pancreatic carcinomas and to a lesser extent in a variety of other cancers. Smad4/DPC4, and the related tumour suppressor Smad2, belong to the SMAD family of proteins that mediate signalling by the TGF-beta/activin/BMP-2/4 cytokine superfamily from receptor Ser/Thr protein kinases at the cell surface to the nucleus. SMAD proteins, which are phosphorylated by the activated receptor, propagate the signal, in part, through homo- and hetero-oligomeric interactions. Smad4/DPC4 plays a central role as it is the shared hetero-oligomerization partner of the other SMADs. The conserved carboxy-terminal domains of SMADs are sufficient for inducing most of the ligand-specific effects, and are the primary targets of tumorigenic inactivation. We now describe the crystal structure of the C-terminal domain (CTD) of the Smad4/DPC4 tumour suppressor, determined at 2.5 A resolution. The structure reveals that the Smad4/DPC4 CTD forms a crystallographic trimer through a conserved protein-protein interface, to which the majority of the tumour-derived missense mutations map. These mutations disrupt homo-oligomerization in vitro and in vivo, indicating that the trimeric assembly of the Smad4/DPC4 CTD is critical for signalling and is disrupted by tumorigenic mutations.
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PMID:A structural basis for mutational inactivation of the tumour suppressor Smad4. 921 96

Ovarian carcinoma is often associated with overexpression of cytokines that may exert autocrine and paracrine growth effects, as well as genetic alterations in (proto)oncogenes and tumour suppressor genes, such as p53. The p53 protein is not only involved in the regulation of cell cycle and apoptosis, it is also involved in the in vitro regulation of IL-6 gene expression. In this study, 30 tumours of patients with a primary diagnosis of human ovarian carcinoma were characterised for p53 expression with immunohistochemistry and analysed for the expression of M-CSF, IL-6, IL-1 beta, IL-11 and TNF-alpha with Northern blotting. Nuclear and cytoplasmic p53 staining was observed in 27% (8/30), cytoplasmic staining in 30% (9/30), and no p53 staining in 43% (13/30) of the tumours. In 70% (21/30) of the tumours, M-CSF mRNA was expressed, in 40% (12/30) TNF-alpha, and in 30% (9/30) IL-6. None of the tumours expressed IL-1 beta or IL-11. The expression of TNF-alpha occurred more frequently in M-CSF positive tumours compared to M-CSF negative tumours (52% (11/21) versus 11% (1/9), P < 0.05). TNF-alpha expression was also associated with better responses to chemotherapy (P < 0.02). M-CSF expression was associated with nuclear p53 staining (P < 0.05). The p53 positive tumours more frequently expressed one or more cytokines (88%) compared with p53 negative tumours (54%, P < 0.05). This study suggests that mutations in the p53 gene might be associated with cytokine overexpression, especially M-CSF.
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PMID:Expression of macrophage colony-stimulating factor (M-CSF), interleukin-6, (IL-6), interleukin-1 beta (IL-1 beta), interleukin-11 (IL-11) and tumour necrosis factor-alpha (TNF-alpha) in p53-characterised human ovarian carcinomas. 947 Aug 14

The NF-kappaB/Rel family of transcription factors regulates a wide variety of genes whose products play a fundamental role in inflammatory and immune responses. The implication of NF-kappaB/Rel proteins and their IkappaB regulatory subunits in the control of cellular growth and oncogenesis, was suggested by the induction of fatal lymphomas in birds by the v-rel oncoprotein, and the rearrangement and amplification of several genes encoding the NF-kappaB/Rel/IkappaB signal transduction factors in human malignancies, primarily of lymphoid origin. Hodgkin's disease (HD) is a lymphoma characterized by a low frequency of malignant Hodgkin and Reed-Sternberg (H/RS) cells in a reactive background of non-neoplastic cells. The peculiar activated phenotype of Hodgkin and Reed-Sternberg cells and their pattern of cytokine secretion are believed to be a consequence of constitutive activation of the NF-kappaB transcription factor. Here, we report the detection of mutations of the IkBa gene, in two HD-derived cell lines and in two out of eight biopsy samples from patients with relapsed Hodgkin's disease. The presence of defective IkappaBalpha is thus likely to explain the constitutive activation of NF-kappaB in these cells and suggests that IkappaBalpha is a tumour suppressor controlling the oncogenic activation of NF-kappaB in Hodgkin and Reed-Sternberg cells.
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PMID:Mutations in the IkBa gene in Hodgkin's disease suggest a tumour suppressor role for IkappaBalpha. 1034 Mar 77

Apoptosis (programmed cell death) of vascular smooth muscle cells (VSMCs) has recently been identified as an important process in a variety of human vascular diseases, including atherosclerosis, arterial injury, and restenosis after angioplasty. VSMC apoptosis is regulated by interactions between the local cell-cell and cytokine environment within the arterial wall, and the expression of pro- and anti-apoptotic proteins by the cell, including death receptors, proto-oncogenes and tumour suppressor genes. This review summarises our current knowledge of the occurrence and mechanisms underlying VSMC apoptosis in atherosclerosis and arterial remodelling.
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PMID:Apoptosis of vascular smooth muscle cells in vascular remodelling and atherosclerotic plaque rupture. 1034 35

Advances in our understanding of the molecular genetics of pancreatic and biliary cancers have given us new targets for therapy using molecular and genetic approaches. Replacement of tumour suppressor gene function using adenoviruses to transfer wild-type p53 and p16 genes can produce dramatic anti-tumour effects, both in vitro and in vivo. Blockade of dominant oncogene function using dominant negative technology may have a particular application for mutated K-ras which occurs almost ubiquitously in pancreatic adenocarcinoma. Genetic prodrug activation therapy using tumour-selective gene promoters to drive the expression of so-called suicide genes is showing remarkable promise. Targeted delivery of such therapeutic constructs may also be possible through knowledge of the expression of surface receptors by particular tumour cell types. Genetic immunomodulation using cytokine genes as well as specific vaccines against tumour-associated antigens are now being brought into clinical trials.
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PMID:Gene therapy for pancreatic and biliary malignancies. 1043 19


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