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 tumour suppressor p53 becomes activated as a transcription factor in response to DNA damage, but the mechanism for this activation is unclear. A good candidate for an upstream activator of p53 is the DNA-dependent protein kinase (DNA-PK) that depends on the presence of DNA breaks for its activity. Here we investigate the link between DNA damage and the activation of DNA-PK and of p53. To determine whether DNA-PK is an upstream mediator of the p53 DNA-damage response, we analysed a severe combined-immunodeficiency (SCID) mouse cell line, SCGR11, and the human glioma cell line M059J . Both cell lines lack any detectable DNA-PK activity. We find that p53 is incapable of binding to DNA in the absence of DNA-PK, that DNA-PK is necessary but not sufficient for activation of p53 sequence-specific DNA binding, and that this activation occurs in response to DNA damage. Our results establish DNA-PK as a link between DNA damage and p53 activation, and reveal the existence of a mammalian DNA-damage-response pathway.
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PMID:DNA-dependent protein kinase acts upstream of p53 in response to DNA damage. 971 37

Ataxia-telangiectasia (A-T) is a multisystem recessive disease characterized by cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency and increased risk of cancer. The ATM gene, responsible for A-T, was recently cloned at human chromosome band 11q22-23, a region of frequent alterations in childhood acute lymphoblastic leukaemia (ALL). Children with A-T frequently develop T-ALL. We investigated 18 T-ALL samples for ATM mutations and loss of heterozygosity (LOH) at the ATM locus. No mutations of ATM were found within the coding region in the 18 T-ALL samples, and LOH at the ATM locus was detected in three. The ATM gene appears to be an infrequently altered tumour suppressor gene in childhood T-ALL.
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PMID:The ATM gene and susceptibility to childhood T-cell acute lymphoblastic leukaemia. 982 31

Ataxia-telangiectasia mutated (ATM) is the product of the gene mutated in the human genetic disorder ataxia-telangeictasia (A-T). It is a 370 kDa protein that is a member of the phosphatidyl inositol 3-kinases superfamily. A-T cells and those derived from Atm-/- mice are characterized by hypersensitivity to ionizing radiation and defective cell cycle checkpoints. Defects are observed at all cell cycle checkpoints in A-T cells post-irradiation including the G1/S interface where ATM plays an important role in the activation of the tumour suppressor gene product p53. Activation leads to the induction of p21/WAF1, inhibition of cyclin-dependent kinase activity, failure to phosphorylate key substrates such as the retinoblastoma protein and consequently G1 arrest. ATM also plays an important role in the regulation and surveillance of meiotic progression. Absence of ATM gives rise to a spectrum of defects including immunodeficiency, neurodegeneration, radiosensitivity and cancer predisposition. It is clear that a better definition of the role of ATM in DNA damage recognition, cell cycle control and cell signalling may assist in the treatment of the progressive neurodegeneration in this syndrome.
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PMID:ATM: the product of the gene mutated in ataxia-telangiectasia. 1046 28

X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency, which most often manifests itself after Epstein-Barr virus (EBV) infection. The main clinical phenotypes include fulminant or fatal infectious mononucleosis, dysgammaglobulinaemia and malignant lymphoma. We have recently cloned the SH2D1A gene, which has been shown to be mutated in approximately 70% of XLP patients. Now we report five novel SH2D1A mutations in patients from five unrelated XLP families. No mutations were found in another three XLP families. In three boys with early onset non-Hodgkin lymphoma (NHL) from two unrelated families a deletion of SH2D1A exon 1 and a splice site mutation were found, respectively. These patients did not show any laboratory or clinical signs of a previous EBV infection. A fourth EBV-uninfected and unrelated boy with a stop mutation in the SH2D1A gene shows only signs of dysgammaglobulinaemia. Development of dysgamma-globulinaemia and lymphoma without evidence of prior EBV infection in four of our patients suggests that EBV is unrelated to these phenotypes, in contrast to fulminant or fatal infectious mononucleosis. The role of SH2D1A as a putative tumour suppressor gene remains to be investigated.
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PMID:Epstein-Barr virus-negative boys with non-Hodgkin lymphoma are mutated in the SH2D1A gene, as are patients with X-linked lymphoproliferative disease (XLP). 1055 88

Aberrant promoter hypermethylation is a mechanism of tumour suppressor gene inactivation. We explored aberrant promoter hypermethylation of multiple genes in 88 human immunodeficiency virus (HIV)-non Hodgkin lymphomas (NHL), 25 post-transplant lymphoproliferative disorders (PTLD) and five common variable immunodeficiency (CVI)-related NHL. Twenty-six of 79 (32.9%) HIV-NHL, eight of 14 (57.1%) PTLD and two of five (40.0%) CVI-NHL showed aberrant hypermethylation of O6-methylguanine-DNA methyltransferase (MGMT). Aberrant hypermethylation of death-associated protein-kinase (DAP-K) occurred in 70 of 84 (83.3%) HIV-NHL, 19 of 25 (72.0%) PTLD and three of five (60.0%) CVI-NHL. These data implicate MGMT and DAP-K hypermethylation in lymphomagenesis of immunodeficient hosts. In particular, promoter hypermethylation of DAP-K represents the most frequent molecular alteration yet identified in immunodeficiency-related lymphomas.
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PMID:Frequent aberrant promoter hypermethylation of O6-methylguanine-DNA methyltransferase and death-associated protein kinase genes in immunodeficiency-related lymphomas. 1461 9

Human SNF5 (hSNF5; INI1, SMARCB1 or BAF47) is a component of the human SWI/SNF chromatin remodelling complex and a tumour suppressor mutated in rhabdoid tumours. It also associates with the integrase of the human immunodeficiency virus (HIV)-1. We show by fluorescence loss in photobleaching that hSNF5 is constantly shuttling between the nucleus and the cytoplasm, raising the question of what the role of hSNF5 is in the cytoplasm. Here, we demonstrate that hSNF5 directly interacts with the GTPase dynamin-2 (DNM2) in the cytoplasm. DNM2 is a large GTPase involved in endocytosis and vesicle dynamics, which has been related to HIV-1 internalization. We show that hSNF5 colocalizes with DNM2 in endocytic vesicles. Depletion of hSNF5, but not of other components of the SWI/SNF complex, destabilizes DNM2 and impairs DNM2-dependent endocytosis. Furthermore, we show that hSNF5 inhibits assembly-stimulated DNM2 GTPase activity but not basal GTPase activity in vitro. Altogether, these results indicate that hSNF5 affects both the stability and the activity of DNM2, uncovering an unexpected role of hSNF5 in modulating endocytosis, and open new perspectives in understanding the role of hSNF5 in tumour genesis.
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PMID:Cytoplasmic interaction of the tumour suppressor protein hSNF5 with dynamin-2 controls endocytosis. 2385 97

Diverse cellular proteins and RNAs are tightly regulated in their subcellular localization to exert their local function. Here we report that the tumour suppressor adenomatous polyposis coli protein (APC) directs the localization and assembly of human immunodeficiency virus (HIV)-1 Gag polyprotein at distinct membrane components to enable the efficient production and spread of infectious viral particles. A proteomic analysis and subsequent biomolecular interaction assay reveals that the carboxyl terminus of APC interacts with the matrix region of Gag. Ectopic expression of APC, but not its familial adenomatous polyposis-related truncation mutant, prominently enhances HIV-1 production. Conversely, the depletion of APC leads to a significant decrease in membrane targeting of viral components, resulting in the severe loss of production of infectious virions. Furthermore, APC promotes the directional assembly of viral components at virological synapses, thereby facilitating cell-to-cell viral transmission. These findings reveal an unexpected role of APC in the directional spread of HIV-1.
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PMID:The tumour suppressor APC promotes HIV-1 assembly via interaction with Gag precursor protein. 2813 56