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 main factors that govern the pathophysiology and malignant growth of multiple myeloma (MM) are genetic defects within the tumour and the interaction between myeloma cells and the bone marrow microenvironment (BMM). This interaction leads to the activation of signalling pathways that promote the expansion of the malignant clone and stimulate neoangiogenesis and osteoclastogenesis. For many years, the cytokine interleukin-6 (IL-6) was considered a central growth factor and was thus believed to play a pivitol role in the pathogenesis of MM. However, increasing numbers of cytokines, chemokines and cell-to-cell contacts provided by the BMM have since been found to support MM cells. It has consistently been demonstrated that oncogenic mutations as well as the BMM stimulate IL-6-independent signalling pathways that protect MM cells from apoptosis. Consequently, multiple targeting of a complex signalling network rather than inhibition of a single pathway or growth factor is required to effectively induce myeloma cell death. Because the tumour suppressor p53 is rarely mutated in MM, non-genotoxic activation of the p53-dependent death pathway could be another attractive therapeutic strategy for this disease. Even though a number of promising new drugs are currently being tested in MM, a comprehensive knowledge of the signalling and survival pathways should pinpoint additional molecular targets and lead to the development of novel and hopefully more effective treatment strategies.
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PMID:Signalling and survival pathways in multiple myeloma. 1679 70

An increasing number of tumour suppressor genes are induced by interferons (IFNs) and may play an important role in the control of cell proliferation induced by this cytokine. In addition, pathways triggered by both tumour suppressors and IFN converge as common targets for non-related tumour viruses. The inhibition of the IFN response by animal viruses is explained by the fundamental role that IFN plays to control virus infection. However, the reasons why many viruses, including those that do not require the replication of the host, target tumour suppressor pathways are varied and are still under investigation. Here we review those findings that support that tumour suppressors may have a role in the control of virus infection.
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PMID:Control of virus infection by tumour suppressors. 1734 39

The von Hippel-Lindau (VHL) gene is located on the short arm of chromosome 3, the mutations of which lead to the development of von Hippel-Lindau disease. The VHL gene is a putative tumour suppressor gene in VHL and a few other conditions, possibly by negative regulation of hypoxia- inducible factor-1 (HIF-1) and the stromal-derived factor-1 (SDF-1) receptor, CXCR4, via which the VHL protein negates angiogenesis and tumour cell migration. The current study investigated the expression of VHL at the mRNA and protein levels in clinical breast tumours and evaluated the impact of VHL on the invasion of human breast cancer cells in vitro. Primary breast cancer samples (n=124), adjacent non-cancerous breast tissues obtained from patients in cohort (n=33) and a panel of human breast cancer cells (n=12) were used. Tissue distribution of VHL protein in human breast cancer tissues was assessed using immunohistochemical analysis, and VHL transcript was determined using quantitative reverse transcription PCR. Breast cancer cell line MDA-MB-231 was transfected with a human VHL expression construct (pCR3-GFP/VHL) to allow forced overexpression of VHL in the cells. Invasiveness and migration of cancer cells were assessed using the Matrigel invasion and Cytodex-2 migration assays. Statistical analysis was performed using the Student's t-test. Our results showed that breast cancer cell lines MCF-7 and ZR-75-1 expressed very high levels of VHL transcripts, but the highly aggressive MDA-MB-231, MDA-MB-435 and MDA-MB-453 expressed either no VHL or a low level. The levels of VHL transcripts were significantly lower in grade 2 and grade 3 tumours (mean +/- SD, 1.36+/-0.55 and 0.9+/-0.37), compared with grade 1 tumours (12.3+/-7.6, p<0.002). Node-positive tumours had lower levels of VHL than node-negative tumours. Although tumours from patients with metastasis and from those who died of breast cancer had low levels of VHL, the most significant reduction in VHL was seen in tumours which developed local recurrence (p=0.03). The staining of VHL protein was most abundant in mammary epithelial cells and moderate in endothelial cells. Tumour cells in breast tissues had low to moderate VHL staining. pCR3-GFP/VHL-transfected MDA-MB-231 (MDA-MB-231VHL+) exhibited a reduced spontaneous in vitro invasiveness (14.8+/-2.7) compared with the control cells (18.4+/-1.4). MDA-MB-231VHL+ cells also lost their invasion response to HGF/SF, an invasion-inducing cytokine. The MDA-MB-231VHL+ cells had substantially reduced motility compared with that of the controls (14.8+/-0.7 for MDA-MB-231VHL+ and 20.7+/-1.2 for the control; p<0.001). Thus, VHL exerts inhibitory effects on the invasive and migratory capacity of breast cancer cells in vitro. Low levels of VHL occur in most aggressive breast tumours. Taken together, VHL is a powerful putative tumour suppressor gene in human breast cancer.
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PMID:The expression of the von Hippel-Lindau gene product and its impact on invasiveness of human breast cancer cells. 1778 94

Many studies have suggested that E3 ubiquitin ligases can behave as either oncogenes or tumour suppressor genes and, recently, it has become clear that the SOCS (suppressor of cytokine signalling) E3 ligases fit this mould. While most cancer-associated E3s regulate the cell cycle or DNA repair, the SOCS proteins inhibit growth factor responses by degrading signalling intermediates such as JAKs (Janus kinases) via the SOCS-box-associated ECS (Elongin-Cullin-SOCS) E3 ligase. Clinical studies have found that (epi)genetic (mutation or methylation) phenomena can occur in many solid tumours and a growing number of clinical findings reveal post-translational modifications that disrupt SOCS function in haematological malignancy. In the present review, we provide a summary of the functions of the SOCS E3s and propose the potential use of members of this family as diagnostic markers and therapeutic targets in cancer.
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PMID:The suppressors of cytokine signalling E3 ligases behave as tumour suppressors. 1848 82

Apoptosis and inflammation generally exert opposite effects on tumorigenesis: apoptosis serves as a barrier to tumour initiation, whereas inflammation promotes tumorigenesis. Although both events are induced by various common stressors, relatively little is known about the stress-induced signalling pathways regulating these events in tumorigenesis. Here, we show that stress-activated MAP3Ks, ASK1 and ASK2, which are involved in cellular responses to various stressors such as reactive oxygen species, differentially regulate the initiation and promotion of tumorigenesis. ASK2 in cooperation with ASK1 functioned as a tumour suppressor by exerting proapoptotic activity in epithelial cells, which was consistent with the reduction in ASK2 expression in human cancer cells and tissues. In contrast, ASK1-dependent cytokine production in inflammatory cells promoted tumorigenesis. Our findings suggest that ASK1 and ASK2 are critically involved in tumorigenesis by differentially regulating apoptosis and inflammation.
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PMID:ASK1 and ASK2 differentially regulate the counteracting roles of apoptosis and inflammation in tumorigenesis. 1921 84

Acquired uniparental disomy (aUPD) is a common feature of cancer genomes, leading to loss of heterozygosity. aUPD is associated not only with loss-of-function mutations of tumour suppressor genes, but also with gain-of-function mutations of proto-oncogenes. Here we show unique gain-of-function mutations of the C-CBL (also known as CBL) tumour suppressor that are tightly associated with aUPD of the 11q arm in myeloid neoplasms showing myeloproliferative features. The C-CBL proto-oncogene, a cellular homologue of v-Cbl, encodes an E3 ubiquitin ligase and negatively regulates signal transduction of tyrosine kinases. Homozygous C-CBL mutations were found in most 11q-aUPD-positive myeloid malignancies. Although the C-CBL mutations were oncogenic in NIH3T3 cells, c-Cbl was shown to functionally and genetically act as a tumour suppressor. C-CBL mutants did not have E3 ubiquitin ligase activity, but inhibited that of wild-type C-CBL and CBL-B (also known as CBLB), leading to prolonged activation of tyrosine kinases after cytokine stimulation. c-Cbl(-/-) haematopoietic stem/progenitor cells (HSPCs) showed enhanced sensitivity to a variety of cytokines compared to c-Cbl(+/+) HSPCs, and transduction of C-CBL mutants into c-Cbl(-/-) HSPCs further augmented their sensitivities to a broader spectrum of cytokines, including stem-cell factor (SCF, also known as KITLG), thrombopoietin (TPO, also known as THPO), IL3 and FLT3 ligand (FLT3LG), indicating the presence of a gain-of-function that could not be attributed to a simple loss-of-function. The gain-of-function effects of C-CBL mutants on cytokine sensitivity of HSPCs largely disappeared in a c-Cbl(+/+) background or by co-transduction of wild-type C-CBL, which suggests the pathogenic importance of loss of wild-type C-CBL alleles found in most cases of C-CBL-mutated myeloid neoplasms. Our findings provide a new insight into a role of gain-of-function mutations of a tumour suppressor associated with aUPD in the pathogenesis of some myeloid cancer subsets.
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PMID:Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. 1967 35

Salmonella are important intracellular pathogens in humans and other animal hosts. IL-24 is a novel tumour suppressor and can mediate induction of Th1-type cytokines from PBMC. However, the immunological consequences of this cytokine during intracellular pathogen infection in vivo remain unclear. In the present study, we used a virulent S. typhimurium C5 infected mouse model of typhoid fever to demonstrate that administration of exogenous IL-24 had a protective effect against the bacteria. The IL-24 glycosylation site mutant, in contrast, showed a decreased protective effect. Furthermore, the protective effect of IL-24 was abrogated in IFN-gamma KO mice. More importantly, we demonstrated that IL-24 predominately stimulated neutrophils to produce IFN-gamma and IL-12, subsequently activating CD8+ T cells both in vivo and in vitro. In addition, IL-24 could induce neutrophils to produce NO. These data indicate that the neutrophils activated by IL-24 may play important roles in host defence against Salmonella infection in vivo. Our findings support the development of a novel cytokine immunotherapy against Salmonella.
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PMID:IL-24 protects against Salmonella typhimurium infection by stimulating early neutrophil Th1 cytokine production, which in turn activates CD8+ T cells. 1983 Jul 36

Interleukin-6 (IL-6) is suggested to have a pathogenic role in the progression of prostate cancer (PC), therefore representing an attractive target for new therapies. However, due to the pleiotropy of this cytokine, targeting IL-6 results in different and unpredictable responses. In order to better understand the mechanisms underlying the different responses to the cytokine, we focused our attention on IL-6 receptors (IL-6Rs) that represent the first element in the cascade of cytokine-activated signalling pathways. IL-6 signal transduction may indeed occur through the membrane IL-6R (classical signalling) and/or through the less studied soluble IL-6R (sIL-6R; IL-6 trans-signalling (IL-6TS)). We provide the first evidence how responses to IL-6 may depend on the different content of IL-6Rs in PC. In particular, the studies of (3)H-thymidine incorporation and exploitation of different approaches (i.e. activation or inhibition of IL-6TS in sIL-6R-negative and -positive cell lines and transfection of IL-6R siRNA) allowed us to demonstrate that IL-6TS specifically accounts for an anti-proliferative effect of the cytokine in three PC cell lines that are known to respond differently to IL-6. Additionally, by applying migration-, scratch- and adhesion assays, we show that IL-6TS increases motility and migration and decreases adhesion of prostate cells facilitating thereby processes that determine metastasis initiation and spread. Finally, by western analyses, we uncovered an IL-6- and sIL-6R-dependent downregulation of the tumour suppressor maspin. Collectively, these data suggest that selective targeting of IL-6TS might allow to refine the currently available experimental anti-IL-6 therapies against PC.
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PMID:Interleukin-6 trans-signalling differentially regulates proliferation, migration, adhesion and maspin expression in human prostate cancer cells. 1996 16

The tumour suppressor p53 is a transcription factor that has evolved the ability to integrate distinct environmental signals including DNA damage, virus infection, and cytokine signaling into a common biological outcome that maintains normal cellular control. Mutations in p53 switch the cellular transcription program resulting in deregulation of the stress responses that normally maintain cell and tissue integrity. Transgenic studies in mice have indicated that changes in the specific activity of p53 can have profound effects not only on cancer development, but also on organism aging. As the specific activity of p53 is regulated at a post-translational level by sets of enzymes that mediate phosphorylation, acetylation, methylation, and ubiquitin-like modifications, it is likely that physiological modifiers of the aging function of p53 would be enzymes that catalyze such covalent modifications. We demonstrate that distinct stress-activated kinases, including ataxia telangiectasia mutated (ATM), casein kinase 1 (CK1) and AMP-activated protein kinase (AMPK), mediate phosphorylation of a key phospho-acceptor site in the p53 transactivation domain in response to diverse stresses including ionizing radiation, DNA virus infection, and elevation in the intracellular AMP/ATP ratio. As diseases linked to aging can involve activation of p53-dependent changes in cellular protective pathways, the development of specific physiological models might further shed light on the role of p53 kinases in modifying age-related diseases.
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PMID:The regulation of p53 by phosphorylation: a model for how distinct signals integrate into the p53 pathway. 2015 32

Natural killer T (NKT) cells modulate immune responses against pathogens and tumours, as well as immunological tolerance. We show here that CYLD, a tumour suppressor with deubiquitinase function, has a pivotal and cell-intrinsic function in NKT cell development. Unlike other known NKT regulators, CYLD is dispensable for intrathymic NKT cell maturation but is obligatory for the survival of immature NKT cells. Interestingly, CYLD deficiency impairs the expression of ICOS, a costimulatory molecule required for the survival and homeostasis of NKT cells, and this molecular defect is associated with attenuated response to an NKT-survival cytokine, IL-7, due to reduced expression of IL-7 receptor. We show, for the first time, that IL-7 induces the expression of ICOS in NKT cells, which is largely dependent on CYLD. Interestingly, loss of CYLD causes constitutive NF-kappaB activation in developing NKT cells, which contributes to their defective IL-7 response and attenuated ICOS expression. These findings establish CYLD as a critical regulator of NKT cell development and provide molecular insights into this novel function of CYLD.
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PMID:Regulation of natural killer T-cell development by deubiquitinase CYLD. 2044 28


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