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 CD95 system plays an important role in lymphocyte homeostasis, has been implicated in the development of lymphoid malignancies, exerts a tumour suppressor function, and contributes to drug-induced cytotoxicity. We hypothesized that mutations of CD95 may occur in childhood B-lineage acute lymphoblastic leukaemia (ALL), a disease known for its constitutive resistance towards CD95-mediated apoptosis. We investigated 32 primary B-lineage ALL of childhood and five B-lineage ALL cell lines. All primary leukaemias expressed CD9 5 and bcl-2 to a variable degree. Most of the leukaemias were resistant towards CD95-mediated apoptosis. However, using SSCP analysis, no mutations in the coding and proximal promoter region could be detected. We conclude that the resistance towards CD95-mediated apoptosis observed in most de novo B-lineage ALL is not caused by mutations of the CD95 death receptor.
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PMID:Mutation analysis of CD95 (APO-1/Fas) in childhood B-lineage acute lymphoblastic leukaemia. 972 99

The candidate tumour suppressor gene, LUCA-15, maps to the lung cancer tumour suppressor locus 3p21.3. Overexpression of an alternative RNA splice variant of LUCA-15 has been shown to retard human Jurkat T cell proliferation and to accelerate CD95-mediated apoptosis. An antisense cDNA to the 3'-UTR of this splice variant was able to suppress CD95-mediated apoptosis. Here, we report that overexpression of LUCA-15 itself suppresses CD95-mediated apoptosis in Jurkat cells. This suppression occurs prior to the final execution stage of the CD95 signalling pathway, and is associated with up-regulation of the apoptosis inhibitory protein Bcl-2. LUCA-15 overexpression is also able to inhibit apoptosis induced by the protein kinase inhibitor staurosporine, but is not able to significantly suppress apoptosis mediated by the topoisomerase II inhibitor etoposide. These findings suggest that LUCA-15 is a selective inhibitor of cell death, and confirm the importance of the LUCA-15 genetic locus in the control of apoptosis.
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PMID:LUCA-15 suppresses CD95-mediated apoptosis in Jurkat T cells. 1142 Jun 83

Many viruses are known to disarm or suppress the cell death machinery of infected cells. Apoptotic cell death can be activated by aggregation of the CD95 cell surface death receptor in sensitive cells, and in most insensitive cells treated with sensitizing agents such as interferon-gamma or inhibitors of protein synthesis. We show that, subsequent to sequestration and inactivation of the p53 tumour suppressor protein, SV40 abrogates p53-dependent, DNA damage-inducible up-regulation of CD95 surface expression. Loss of surface up-regulation of CD95 after sub-lethal mitomycin C treatment resulted in an impaired enhancement of both caspase-8 cleavage and apoptotic cell death following CD95 aggregation. We conclude that infection of human cells with SV40 virus strongly inhibits DNA damage-induced enhancement of CD95-mediated apoptosis.
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PMID:Simian virus-40 infection inhibits DNA damage-induced enhancement of CD95 expression and function. 1180 62

Cancers of the lung and pleura remain a major cause of cancer deaths, both in men and women, with strong causal relationships between cigarette smoking and asbestos fibres, and deaths from lung cancer and mesothelioma, respectively. The poor survival rates for small cell lung cancer and mesotheliomas argue powerfully for greater understanding of mechanisms of carcinogenesis, genetic abnormalities and the role of tumour suppressor genes and proteins in carcinomas of the lung and pleura. Despite progress in the development of newer cytotoxic drugs, lung cancer remains a lethal disease. Chemotherapy and radiotherapy produce only a modest improvement in survival of patients with advanced disease. Increased knowledge of molecular mechanisms of lung cancer and apoptosis are providing opportunities for treating lung cancer with new classes of molecularly targeted drugs. These novel therapies should target the abnormalities in lung cancer by maximizing the effects of anti-tumour molecules, with minimal side effects on normal tissues. Of the several molecular targets, those receiving attention are p53 gene replacement, Bcl-2 downregulation, apoptosis by induced by TNF, the FAS/CD95 receptor system and TRAIL, and inhibition of NF-kappaB. Although several studies have shown benefits, there is a need for well planned clinical trials of drugs that target the apoptotic cascade. Stem cell therapy and gene replacement offer the prospect of novel approaches that are likely in the near future to play a definitive role in the treatment of advanced lung cancer. Furthermore, with their apparent minimal toxicity to normal tissues, the newer molecular targets represent attractive investigational directions for innovative cancer therapies.
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PMID:Molecular genetics and mechanisms of apoptosis in carcinomas of the lung and pleura: therapeutic targets. 1803 30