Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q06643 (non-Hodgkin's lymphoma)
 11,307 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ubiquitin-mediated degradation of proteins in numerous cellular processes, such as turnover and quality control of proteins, cell cycle and apoptosis, transcription and cell signaling, immune response and antigen presentation, and inflammation and development makes the ubiquitin-proteosome systems a very interesting target for various therapeutic interventions. Proteosome inhibitors were first synthesized as tools to probe the function and specificity of this particle's proteolytic activities. Most synthetic inhibitors rely on a peptide base, which mimics a protein substrate, attached at a COOH terminal "warhead." Notable warheads include boronic acids, such as bortezomib and epoxy ketones, such as carfilzomib. A variety of natural products also inhibit the proteosome that are not peptide-based, most notably lactacystin, that is related to NPI-0052, or salinosporamide A, another inhibitor in clinical trials. The possibility that proteosome inhibitors could be drug candidates was considered after studies showed that they induced apoptosis in leukemic cell lines. The first proteasome inhibitor in clinical application, bortezomib showed activity in non-small-cell lung and androgen-independent prostate carcinoma, as well as MM and mantle cell and follicular non-Hodgkin's lymphoma. It is now licensed for the treatment of newly diagnosed as well as relapsed/progressive MM and has had a major impact on the improvement in the treatment of MM in the last few years.
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PMID:Bortezomib. 2475 2

Mantle cell lymphoma (MCL) is an uncommon, incurable B-cell non-Hodgkin's lymphoma that afflicts the elderly. There is no standard course of treatment, with options varying from observation in asymptomatic patients to aggressive induction/consolidation regimens in younger patients with rapidly progressive disease. Emerging data regarding the role of the ubiquitin-proteasome system, B-cell receptor and mTOR signaling pathways, cell cycle regulation, and epigenetic and immune-modulation in the pathogenesis of MCL have resulted in the development of novel therapies, with a shift away from conventional cytotoxic chemotherapy to relatively less toxic, more targeted treatment. The challenge now is to determine the optimal sequence and combination of the various available and emerging therapies for use in patients with MCL.
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PMID:Mantle cell lymphoma: taking therapeutic advantage of new insights into the biology. 2502 97

Tumor necrosis factor receptor (TNFR) associated factor 1 (TRAF1) is a signaling adaptor first identified as part of the TNFR2 signaling complex. TRAF1 plays a key role in pro-survival signaling downstream of TNFR superfamily members such as TNFR2, LMP1, 4-1BB, and CD40. Recent studies have uncovered another role for TRAF1, independent of its role in TNFR superfamily signaling, in negatively regulating Toll-like receptor and Nod-like receptor signaling, through sequestering the linear ubiquitin assembly complex, LUBAC. TRAF1 has diverse roles in human disease. TRAF1 is overexpressed in many B cell related cancers and single nucleotide polymorphisms (SNPs) in TRAF1 have been linked to non-Hodgkin's lymphoma. Genome wide association studies have identified an association between SNPs in the 5' untranslated region of the TRAF1 gene with increased incidence and severity of rheumatoid arthritis and other rheumatic diseases. The loss of TRAF1 from chronically stimulated CD8 T cells results in desensitization of the 4-1BB signaling pathway, thereby contributing to T cell exhaustion during chronic infection. These apparently opposing roles of TRAF1 as both a positive and negative regulator of immune signaling have led to some confusion in the literature. Here we review the role of TRAF1 as a positive and negative regulator in different signaling pathways. Then we discuss the role of TRAF1 in human disease, attempting to reconcile seemingly contradictory roles based on current knowledge of TRAF1 signaling and biology. We also discuss avenues for future research to further clarify the impact of TRAF1 in human disease.
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PMID:TRAF1 Signaling in Human Health and Disease. 3061 26


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