Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ewing's sarcoma/primitive neuroectodermal tumor (EWS/PNET) has a characteristic chimeric oncogene EWS-FLI1, which results from chromosomal translocation t (11; 22), that is believed to initiate tumorigenesis of EWS/PNET. However, the specific details of EWS/PNET oncogenesis and exact role of EWS-FLI1 remain largely unknown. In this study we explored the role of EWS-FLI1 in tumor differentiation using an embryonal carcinoma cell line P19 as a model, with forced expression of EWS-FLI1 in these cells. EWS-FLI1 has been reported to promote neural differentiation in fibroblasts, mesenchymal stem cells and rhabdomyosarcoma cells. We show forced expression of EWS-FLI1 causes absence of retinoic acid-induced neural morphology, and decreases expression of neural-specific proteins MAPT and NCAM. Critical transcriptional factors for neural differentiation and stem cells are also altered in the presence of EWS-FLI1, including decreases in levels of Oct-3 and Pax-6, and an increase in the level of Id2, which is a target of EWS-FLI1. Increased proliferation and decreased apoptotic rates are also observed in P19 cells with forced expression of EWS-FLI1. Our results raise the possibility that arrest of neural differentiation by forced expression of EWS-FLI1 as observed in this study may result from dysregulation of the cell cycle and cell proliferation. Taken together, our results demonstrate that the modulation of neural differentiation in P19 cells which have a stem cell-like pluripotency in vitro can provide a novel model system to study the neural differentiation effects of EWS-FLI1 tumorigenesis of EWS/PNET.
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PMID:Neural differentiation arrest in embryonal carcinoma cells with forced expression of EWS-FLI1. 1862 80

Mutations in fused in sarcoma (FUS) in a subset of patients with amyotrophic lateral sclerosis (ALS) linked this DNA/RNA-binding protein to neurodegeneration. Most of the mutations disrupt the nuclear localization signal which strongly suggests a loss-of-function pathomechanism, supported by cytoplasmic inclusions. FUS-positive neuronal cytoplasmic inclusions are also found in a subset of patients with frontotemporal lobar degeneration (FTLD). Here, we discuss recent data on the role of alternative splicing in FUS-mediated pathology in the central nervous system. Several groups have shown that FUS binds broadly to many transcripts in the brain and have also identified a plethora of putative splice targets; however, only ABLIM1, BRAF, Ewing sarcoma protein R1 (EWSR1), microtubule-associated protein tau (MAPT), NgCAM cell adhesion molecule (NRCAM), and netrin G1 (NTNG1) have been identified in at least three of four studies. Gene ontology analysis of all putative targets unanimously suggests a role in axon growth and cytoskeletal organization, consistent with the altered morphology of dendritic spines and axonal growth cones reported upon loss of FUS. Among the axonal targets, MAPT/tau and NTNG1 have been further validated in biochemical studies. The next challenge will be to confirm changes of FUS-mediated alternative splicing in patients and define their precise role in the pathophysiology of ALS and FTLD.
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PMID:FUS-mediated alternative splicing in the nervous system: consequences for ALS and FTLD. 2397 90

Frontotemporal dementia (FTD) encompasses a spectrum of clinical syndromes characterized by progressive executive, behavioural and language dysfunction. The various FTD spectrum disorders are associated with brain accumulation of different proteins: tau, the transactive response DNA binding protein of 43 kDa (TDP43), or fused in sarcoma (FUS) protein, Ewing sarcoma protein and TATA-binding protein-associated factor 15 (TAF15) (collectively known as FET proteins). Approximately 60% of patients with FTD have autosomal dominant mutations in C9orf72, GRN or MAPT genes. Currently available treatments are symptomatic and provide limited benefit. However, the increased understanding of FTD pathogenesis is driving the development of potential disease-modifying therapies. Most of these drugs target pathological tau - this category includes tau phosphorylation inhibitors, tau aggregation inhibitors, active and passive anti-tau immunotherapies, and MAPT-targeted antisense oligonucleotides. Some of these therapeutic approaches are being tested in phase II clinical trials. Pharmacological approaches that target the effects of GRN and C9orf72 mutations are also in development. Key results of large clinical trials will be available in a few years. However, clinical trials in FTD pose several challenges, and the development of specific brain imaging and molecular biomarkers could facilitate the recruitment of clinically homogenous groups to improve the chances of positive clinical trial results.
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PMID:Development of disease-modifying drugs for frontotemporal dementia spectrum disorders. 3220 98