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)

Considerable evidence is gathering for the involvement of vascular endothelial growth factor (VEGF) in the vascularization and growth of primary tumours as well as in the formation of metastases. The expression of VEGF depends on activated oncogenes and inactivated tumour suppressor genes as well as several other factors (e.g. growth factors, tumour promoters and hypoxia). Substantial expression of the receptors for VEGF is restricted mainly to the tumour blood vessels. The causal involvement of this angiogenic factor in the progression of disease has been successfully evaluated by means of monoclonal antibodies against VEGF, dominant-negative receptor mutants and the use of antisense oligonucleotides against the VEGF mRNA. Thus, the VEGF signalling system seems to be an appropriate target to inhibit tumour angiogenesis and metastases formation.
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PMID:VEGF-mediated tumour angiogenesis: a new target for cancer therapy. 852 39

Von Hippel-Lindau disease (VHL) is caused by germline mutations in the VHL tumour suppressor gene. Tumour development in this setting is due to loss or inactivation of the remaining wild-type VHL allele. The VHL gene product (pVHL) resides primarily in the cytoplasm. A frequently mutated region of pVHL can bind to complexes containing elongin B, elongin C and Cul2. Loss of pVHL leads to an inappropriate accumulation of hypoxia-inducible mRNAs, such as the mRNA encoding vascular endothelial growth factor (VEGF), under normoxic conditions. This finding is most likely to account for the hypervascular nature of VHL-associated neoplasms. Current studies are focussed on understanding if and how binding to elongins and Cul2 is linked to the ability of pVHL to regulate hypoxia-inducible mRNAs. In this regard, it is perhaps noteworthy that elongin C and Cul2 are homologous to yeast proteins Skp1 and Cdc53. These latter proteins participate in the formation of complexes that target certain proteins for ubiquitination.
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PMID:Functions of the von Hippel-Lindau tumour suppressor protein. 968 55

Hypoxia is present in several areas of malignant tumours and is thought to result from an inadequate rate of tumour angiogenesis, vascular collapse, or both. The presence and extent of these hypoxic tumour microenvironments have recently been shown to influence tumour progression by regulating both tumour cell survival and the expression of key angiogenic molecules. Recent studies have suggested that mutations in the tumour suppressor gene, p53, may play an important role in regulating the adaptive response of tumour cells to hypoxia by enhancing their survival and release of proangiogenic factors such as vascular endothelial growth factor. It has even been suggested that hypoxia may select for the survival of the more malignant clones harbouring such genetic defects as mutations in p53. Recently, the transcription factor, NFkB, has also been implicated as a novel mediator of the effects of hypoxia and reoxygenation in tumour cells. This article reviews some of the molecular mechanisms subserving the responses of tumour cells to hypoxic stress, particularly the role and relation of NFkB and p53 in regulating this phenomenon.
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PMID:Response of tumour cells to hypoxia: role of p53 and NFkB. 971 87

Advanced malignancy in tumours represents the phenotypic endpoint of successive genetic lesions that affect the function and regulation of oncogenes and tumour-suppressor genes. The established tumour is maintained through complex and poorly understood host-tumour interactions that guide processes such as angiogenesis and immune sequestration. The many different genetic alterations that accompany tumour genesis raise questions as to whether experimental cancer-promoting mutations remain relevant during tumour maintenance. Here we show that melanoma genesis and maintenance are strictly dependent upon expression of H-RasV12G in a doxycycline-inducible H-Ras12G mouse melanoma model null for the tumour suppressor INK4a. Withdrawal of doxycycline and H-RasV12G down-regulation resulted in clinical and histological regression of primary and explanted tumours. The initial stages of regression involved marked apoptosis in the tumour cells and host-derived endothelial cells. Although the regulation of vascular endothelial growth factor (VEGF) was found to be Ras-dependent in vitro, the failure of persistent endogenous and enforced VEGF expression to sustain tumour viability indicates that the tumour-maintaining actions of activated Ras extend beyond the regulation of VEGF expression in vivo. Our results provide genetic evidence that H-RasV12G is important in both the genesis and maintenance of solid tumours.
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PMID:Essential role for oncogenic Ras in tumour maintenance. 1044 Mar 78

Fibroblast growth factor-2 (FGF-2) is a powerful mitogen and angiogenic factor whose expression is strongly regulated at the translational level. The constitutive upregulation of FGF-2 isoforms in transformed cells prompted us to investigate the post-transcriptional effects of a tumour suppressor, p53, on FGF-2 expression. We show here in human primary skin fibroblasts that the cell density-dependent variation of FGF-2 mRNA translatability was inversely correlated with endogenous p53 expression. Transient cell transfection revealed an inhibitory effect of wild-type p53 on the expression of chimeric FGF--CAT proteins. RNAse mapping experiments ruled out any effect of p53 on FGF--CAT mRNA accumulation, suggesting a translational inhibition. This inhibition was mediated by the FGF-2 mRNA leader, but not by vascular endothelial growth factor or platelet derived growth factor mRNA leaders. Neither p53-like protein p73, nor p21/waf had any inhibitory activity. Furthermore a set of hot spot mutants of p53 bearing mutations in the DNA binding domain had no post-transcriptional inhibitory effect. In contrast a p53 mutant of the transactivating domain was still able to block FGF--CAT expression, indicating that the post-transcriptional activity of p53 described here was independent of the trans-activation of target genes. Such data reveal a novel mechanism by which p53 efficiently blocks the expression of a major proliferating, anti-apoptotic and angiogenic gene.
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PMID:Tumour suppressor p53 inhibits human fibroblast growth factor 2 expression by a post-transcriptional mechanism. 1131 15

Inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene product pVHL is the cause of inherited VHL disease and is associated with sporadic kidney cancer. pVHL is found in a multiprotein complex with elongins B/C, Cul2, and Rbx1 forming an E3 ubiquitin ligase complex called VEC. This modular enzyme targets the alpha subunits of hypoxia-inducible factor (HIF) for ubiquitin-mediated destruction. Consequently, tumour cells lacking functional pVHL overproduce the products of HIF-target genes such as vascular endothelial growth factor (VEGF), which promotes angiogenesis. This likely accounts for the hypervascular nature of VHL-associated neoplasms. Although pVHL has been linked to the cell-cycle, differentiation, and the regulation of extracellular matrix assembly, microenvironment pH, and tissue invasiveness, this review will focus on the recent insights into the molecular mechanisms governing the E3 ubiquitin ligase function of VEC.
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PMID:Playing Tag with HIF: The VHL Story. 1248 77

All neoplasms require angiogenesis and resulting neovascularity for growth beyond 1 mm(2). Quantitative microvessel density (MVD) has been shown to provide staging and prognostic significance in human prostate cancer (CaP). recently, it has been demonstrated that loss of the wild-type allele of the p53 tumour suppressor gene results in reduced expression of thrombospondin-1 (TSP-1), a potent inhibitor of angiogenesis. There is also an increased expression of vascular endothelial growth factor which promotes neovascularization. p53 gene mutation and MVD were investigated in men with prostate cancer. Sections from 103 radical prostatectomy cases were evaluated with immunohistochemistry to detect mutant p53 proteins. Quantitative MVD was performed on the cases exhibiting p53 positive staining and compared with negative fields of similar Gleason grade on the same histologic sections. Twenty of the 103 cases (19.4%) revealed positive p53 staining nuclei. In 19 of these 20 cases, the MVD in p53 positive areas was greater than corresponding control regions (overall P<0.0001). Extent of p53 abnormality, as well as MVD, correlated with pathologic stage. These data suggest that mutations of the p53 tumour suppressor gene may be associated with increased angiogenesis in CaP. In addition to providing staging and prognostic information, this relationship potentially has therapeutic implications.
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PMID:The relation of p53 protein nuclear accumulation and angiogenesis in human prostatic carcinoma. 1249 32

The accuracy and reliability of in situ studies may be compromised by qualitative interpretations. Quantitation imposes a greater degree of objectivity, is more reproducible, and facilitates the clarity of definitions. The aim of this study was to validate the utility of laser imaging systems for the in situ quantitative analysis of gene expression in tissue microarrays. Immunofluorescence was employed to quantify the expression of the tumour suppressor p53, a marker of proliferation (Ki67), an endothelial cell marker (CD31), and the mismatch repair proteins human Mut L homologue 1 and human Mut S homologue 2 in an arrayed series of colorectal tissues (n = 110). Quantitative data on this panel of antigens were compared objectively with qualitative scoring of immunohistochemical chromogen deposition. In addition, the expression of vascular endothelial growth factor (VEGF)-A, placental growth factor, hepatocyte growth factor, and c-Met mRNA was quantified by phosphor image analysis of in situ hybridization reactions. The quantified data on p53, Ki67, and CD31 expression were significantly associated with the pathologist's score (p < or = 0.001). While hepatocyte growth factor and placental growth factor were not up-regulated, c-Met expression was increased up to 2.5-fold and the median VEGF-A expression was elevated 4-fold (p = 0.003) in this series of colorectal tumours. Laser imaging systems are therefore feasible for high-throughput, quantitative profiling of tissue microarrays.
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PMID:Quantitative analysis of colorectal tissue microarrays by immunofluorescence and in situ hybridization. 1289 93

Humans, like other complex aerobic organisms, possess highly evolved systems for the delivery of dioxygen to all the cells of the body. These systems are regulated since excessive levels of dioxygen are toxic. In animals hypoxia causes an increase in the transcription levels of specific genes, including those encoding for vascular endothelial growth factor and erythropoietin. At the transcriptional level, the hypoxic response is mediated by hypoxia-inducible factor (HIF), an alpha,beta-heterodimeric protein. HIF-beta is constitutively present, but HIF-alpha levels are regulated by dioxygen. Under hypoxic conditions, levels of HIF-alpha rise, allowing its dimerization with HIF-beta and enabling transcriptional activation. Under normoxic conditions both the level of HIF-alpha and its ability to enable transcription are directly controlled by its post-translational oxidation by oxygenases. Hydroxylation of HIF-alpha at either of two conserved prolyl residues enables its recognition by the von Hippel-Lindau tumour suppressor protein which targets it for proteasomal degradation. Hydroxylation of an asparaginyl residue in the C-terminal transactivation domain of HIF-alpha directly prevents its interaction with the coactivator p300 from the transcription complex. Hydroxylation of HIF-alpha is catalysed by members of the iron (II) and 2-oxoglutarate dependent oxygenase family. In humans, three prolyl-hydroxylase isozymes (PHD1-3, for prolyl hydroxylase domain enzymes) and an asparaginyl hydroxylase (FIH, for factor inhibiting HIF) have been identified. Recent studies have identified additional post-translational modifications of HIF-alpha including acetylation and phosphorylation. Modulation of the HIF mediated hypoxic response is of potential use in a wide range of disease states including cardiovascular disease and cancer. Here we review current knowledge of the HIF pathway focusing on its regulation by dioxygen and discussion of potential targets and challenges in attempts to modulate the pathway for medicinal application.
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PMID:Modulating the hypoxia-inducible factor signaling pathway: applications from cardiovascular disease to cancer. 1503 87

Much progress has recently been obtained in the classification and characterization of RCC by using cytogenetic, gene microarray and proteomic techniques. Pivotal for the understanding of the progression of malignancy of clear cell renal cell carcinomas are findings connecting its biology to inactivation of the von Hippel-Lindau tumour suppressor gene product (VHLp), found in most CC-RCCs. Disruption of VHLp function appears to be involved in altered cell cycle control, resistance to hypoxia, hyperangiogenesis and changes in the organization of cytoskeletal and extracellular matrix proteins in RCC. These changes are reflected in the overexpression of the vascular endothelial growth factor (VEGF) and the subunits of hypoxia-inducible factor (HIF), and other angiogenetic and metastasis-promoting factors. Other changes related to progression of malignancy in RCC are the upregulation of proinflammatory cytokines and changes in cell adhesion proteins.
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PMID:Progression of malignancy in clear cell renal cell carcinomas. 1528 62


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