Journal articles: 'Fused in Sarcoma/Translocated in Liposarcoma'

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Yang, Shu, Sadaf T. Warraich, Garth A. Nicholson, and Ian P. Blair. "Fused in sarcoma/translocated in liposarcoma: A multifunctional DNA/RNA binding protein." International Journal of Biochemistry & Cell Biology 42, no. 9 (September 2010): 1408–11. http://dx.doi.org/10.1016/j.biocel.2010.06.003.

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Aoki, Masashi. "Amyotrophic lateral sclerosis (ALS) with the mutations in the fused in sarcoma/translocated in liposarcoma gene." Rinsho Shinkeigaku 53, no. 11 (2013): 1080–83. http://dx.doi.org/10.5692/clinicalneurol.53.1080.

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Tan, A. Y., T. R. Riley, T. Coady, H. J. Bussemaker, and J. L. Manley. "TLS/FUS (translocated in liposarcoma/fused in sarcoma) regulates target gene transcription via single-stranded DNA response elements." Proceedings of the National Academy of Sciences 109, no. 16 (March 29, 2012): 6030–35. http://dx.doi.org/10.1073/pnas.1203028109.

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Stronati, Eleonora, Stefano Biagioni, Mario Fiore, Mauro Giorgi, Giancarlo Poiana, Camilla Toselli, and Emanuele Cacci. "Wild-Type and Mutant FUS Expression Reduce Proliferation and Neuronal Differentiation Properties of Neural Stem Progenitor Cells." International Journal of Molecular Sciences 22, no. 14 (July 15, 2021): 7566. http://dx.doi.org/10.3390/ijms22147566.

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Nervous system development involves proliferation and cell specification of progenitor cells into neurons and glial cells. Unveiling how this complex process is orchestrated under physiological conditions and deciphering the molecular and cellular changes leading to neurological diseases is mandatory. To date, great efforts have been aimed at identifying gene mutations associated with many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Mutations in the RNA/DNA binding protein Fused in Sarcoma/Translocated in Liposarcoma (FUS/TLS) have been associated with motor neuron degeneration in rodents and humans. Furthermore, increased levels of the wild-type protein can promote neuronal cell death. Despite the well-established causal link between FUS mutations and ALS, its role in neural cells remains elusive. In order to shed new light on FUS functions we studied its role in the control of neural stem progenitor cell (NSPC) properties. Here, we report that human wild-type Fused in Sarcoma (WT FUS), exogenously expressed in mouse embryonic spinal cord-derived NSPCs, was localized in the nucleus, caused cell cycle arrest in G1 phase by affecting cell cycle regulator expression, and strongly reduced neuronal differentiation. Furthermore, the expression of the human mutant form of FUS (P525L-FUS), associated with early-onset ALS, drives the cells preferentially towards a glial lineage, strongly reducing the number of developing neurons. These results provide insight into the involvement of FUS in NSPC proliferation and differentiation into neurons and glia.

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Yasuda, Kyota, Huaye Zhang, David Loiselle, Timothy Haystead, Ian G. Macara, and Stavroula Mili. "The RNA-binding protein Fus directs translation of localized mRNAs in APC-RNP granules." Journal of Cell Biology 203, no. 5 (December 2, 2013): 737–46. http://dx.doi.org/10.1083/jcb.201306058.

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RNA localization pathways direct numerous mRNAs to distinct subcellular regions and affect many physiological processes. In one such pathway the tumor-suppressor protein adenomatous polyposis coli (APC) targets RNAs to cell protrusions, forming APC-containing ribonucleoprotein complexes (APC-RNPs). Here, we show that APC-RNPs associate with the RNA-binding protein Fus/TLS (fused in sarcoma/translocated in liposarcoma). Fus is not required for APC-RNP localization but is required for efficient translation of associated transcripts. Labeling of newly synthesized proteins revealed that Fus promotes translation preferentially within protrusions. Mutations in Fus cause amyotrophic lateral sclerosis (ALS) and the mutant protein forms inclusions that appear to correspond to stress granules. We show that overexpression or mutation of Fus results in formation of granules, which preferentially recruit APC-RNPs. Remarkably, these granules are not translationally silent. Instead, APC-RNP transcripts are translated within cytoplasmic Fus granules. These results unexpectedly show that translation can occur within stress-like granules. Importantly, they identify a new local function for cytoplasmic Fus with implications for ALS pathology.

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Gardiner, Mary, Rachel Toth, Franck Vandermoere, Nicholas A. Morrice, and John Rouse. "Identification and characterization of FUS/TLS as a new target of ATM." Biochemical Journal 415, no. 2 (September 25, 2008): 297–307. http://dx.doi.org/10.1042/bj20081135.

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ATM (ataxia-telangiectasia mutated), ATR (ATM- and Rad3-related) and DNA-PK (DNA-dependent protein kinase), important regulators of genome stability, belong to the PIKK (phosphoinositide 3-kinase-like kinase) family of protein kinases. In the present study, DNA-affinity chromatography was used to identify DNA-binding proteins phosphorylated by these kinases. This resulted in the identification of FUS (fused in sarcoma)/TLS (translocated in liposarcoma) as an in vitro target of the PIKKs. FUS is a member of the Ewing's sarcoma family of proteins that appears to play a role in regulating genome stability, since mice lacking FUS show chromosomal instability and defects in meiosis. The residues in FUS that are phosphorylated in vitro and in vivo were identified, and phospho-specific antibodies were generated to demonstrate that FUS becomes phosphorylated at Ser42in vivo, primarily in response to agents that cause DSBs (double-strand breaks). DSB-induced FUS phosphorylation in vivo at Ser42 requires ATM and not DNA-PK. Although Ser42 is retained in the oncogenic FUS–CHOP [C/EBP (CCAAT/enhancer-binding protein)-homologous protein 10] fusion generated by a t(12;16)(q13;p11) chromosomal translocation, Ser42 in FUS–CHOP is not phosphorylated after DNA damage. These results identify FUS as a new target of the ATM-signalling pathway and strengthen the notion that FUS regulates genome stability.

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Yu, Yang, Shuhei Hayashi, Xianbin Cai, Chongye Fang, Wei Shi, Hiroko Tsutsui, and Jun Sheng. "Pu-Erh Tea Extract Induces the Degradation of FET Family Proteins Involved in the Pathogenesis of Amyotrophic Lateral Sclerosis." BioMed Research International 2014 (2014): 1–12. http://dx.doi.org/10.1155/2014/254680.

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FET family proteins consist of fused in sarcoma/translocated in liposarcoma (FUS/TLS), Ewing's sarcoma (EWS), and TATA-binding protein-associated factor 15 (TAF15). Mutations in the copper/zinc superoxide dismutase (SOD1), TAR DNA-binding protein 43 (TDP-43), and FET family proteins are associated with the development of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. There is currently no cure for this disease and few effective treatments are available. Epidemiological studies indicate that the consumption of tea is associated with a reduced risk of developing neurodegenerative diseases. The results of this study revealed that components of a pu-erh tea extract (PTE) interacted with FET family proteins but not with TDP-43 or SOD1. PTE induced the degradation of FET family proteins but had no effects on TDP-43 or SOD1. The most frequently occurring ALS-linked FUS/TLS mutant protein, R521C FUS/TLS, was also degraded in the presence of PTE. Furthermore, ammonium chloride, a lysosome inhibitor, but not lactacystin, a proteasome inhibitor, reduced the degradation of FUS/TLS protein by PTE. PTE significantly reduced the incorporation of R521C FUS/TLS into stress granules under stress conditions. These findings suggest that PTE may have beneficial health effects, including preventing the onset of FET family protein-associated neurodegenerative diseases and delaying the progression of ALS by inhibiting the cytoplasmic aggregation of FET family proteins.

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Bao, Le, Lei Yuan, Pengfei Li, Qingyun Bu, Aijun Guo, Hui Zhang, Ning Cui, and Bin Liu. "A FUS-LATS1/2 Axis Inhibits Hepatocellular Carcinoma Progression via Activating Hippo Pathway." Cellular Physiology and Biochemistry 50, no. 2 (2018): 437–51. http://dx.doi.org/10.1159/000494155.

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Background/Aims: The roles and related mechanisms of RNA binding protein FUS (fused in sarcoma/translocated in liposarcoma) are unclear in numerous cancers, including hepatocellular carcinoma (HCC). Methods: Quantitative reverse transcription PCR (qRT-PCR), western blot, cell viability, transwell migration and invasion, tumor spheres formation and in vivo tumor formation assays were used to examine the effects of FUS on HCC progression in HuH7 and MHCC97 cells. Additionally, transcriptome analysis based on RNA-sequencing data, qRT-PCR, western blots, luciferase reporter and RNA binding protein immunoprecipitation (RIP) assays were used to explore the LATS1/2 (large tumor suppressor kinases 1/2)-related mechanisms contributing to FUS functions. Finally, qRT-PCR and western blot analysis were used to detect the levels of FUS and LATS1/2 in HCC and adjacent normal tissues, and the correlation between them in HCC tissues. Results: Overexpression of FUS decreased cell viability, migration, invasion and stemness. Moreover, FUS interacted and stabilized LATS1/2 stability, and thus promoted LATS1/2 expression and activated Hippo pathway. Finally, FUS and LAST1/2 levels were positively correlated and significantly down-regulated in HCC tissues. Conclusion: We demonstrate that FUS/LATS1/2 axis inhibits HCC progression via activating Hippo pathway.

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Yu, Qiongqiong, Yajing Du, Suping Wang, and Xiaofei Zheng. "LncRNA PART1 promotes cell proliferation and inhibits apoptosis of oral squamous cell carcinoma by blocking EZH2 degradation." Journal of Biochemistry 169, no. 6 (March 16, 2021): 721–30. http://dx.doi.org/10.1093/jb/mvab026.

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Abstract Long non-coding RNAs (lncRNAs) have been considered as novel regulators in oral squamous cell carcinoma (OSCC). Enhancer of zeste homolog 2 (EZH2) can act as an oncogene in OSCC. This study intended to investigate whether lncRNA prostatic androgen-regulated transcription 1 (PART1) can exert its role in OSCC by regulating EZH2. The expression of PART1 in OSCC samples, tumour tissues or OSCC cell lines was detected by qRT-PCR. The proliferation and apoptosis of OSCC cells were detected by CCK-8 and flow cytometry assays, respectively. The expression of PART1 and EZH2 was highly expressed in clinical OSCC tumours and cell lines. The expression level of PART1 was positively correlated to the size, clinical stage and node metastasis of OSCC patients. Functionally, PART1 knockdown inhibited proliferation and facilitated apoptosis of OSCC cells. Mechanically, fused in sarcoma/translocated in liposarcoma (FUS) interacted with PART1 and EZH2. In addition, PART1 knockdown reduced the mRNA expression of EZH2, which was offset by FUS overexpression. The overexpression of FUS abrogated the effects of PART1 silence on proliferation and apoptosis of OSCC cells. The in vivo experiment revealed that PART1 knockdown inhibited tumour growth of OSCC cells in nude mice. This study indicated that PART1 exerts a carcinogenic role in OSCC by enhancing the stability of EZH2 protein.

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Sugawara, Takeaki, Hideyuki Oguro, and Atsushi Iwama. "TET Family Oncogene Fus Is Essential for the Maintenance of Self-Renewing Hematopoietic Stem Cells." Blood 114, no. 22 (November 20, 2009): 2529. http://dx.doi.org/10.1182/blood.v114.22.2529.2529.

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Abstract Abstract 2529 Poster Board II-506 A Proto-oncogene FUS (fusion derived from malignant liposarcoma), also known as TLS (translocated in liposarcoma), was originally identified in chromosomal translocation of human soft tissue sarcoma. FUS is also known to be fused with an ETS family transcription factor ERG in human myeloid leukemia with t(16;21) which is associated with poor prognosis. Based on its protein structure, DNA- and RNA-binding activity and involvement in many human cancers as the fusion with various transcription factors, FUS is now grouped with EWS and TAFII68 into TET (FET) oncogene family. Multiple functions have been postulated for FUS, including non-coding-RNA-mediated transcriptional repression, posttranscriptional RNA processing and the maintenance of genomic integrity. Fus-deficient (Fus−/−) mice showed a non-cell-autonomous defect in B lymphocyte development, defective B cell activation and increased sensitivity to radiation in previous studies. However, its physiological function in hematopoiesis remains unknown. In this study we performed detailed analyses of Fus−/− hematopoietic stem cells (HSCs). Fus−/− fetal livers at embryonic day 14.5 exhibited a mild reduction in numbers of hematopoietic stem and progenitor cells compared with the wild type. Disruption of Fus, however, did not grossly affect proliferation or differentiation of hematopoietic progenitors. Of note, Fus−/− HSCs had significantly reduced repopulating activity of hematopoiesis in competitive repopulation assays, and did not repopulate hematopoiesis at all in tertiary recipients. Moreover, Fus−/− HSCs were highly sensitive to radiation both in vitro and in vivo and showed a drastic reduction in numbers in recipient mice after sublethal irradiation. All these findings implicate Fus in the maintenance and radioprotection of HSCs. Studies of chromosome stability, telomere length, apoptosis and levels of reactive oxigen species (ROS) appeared not accountable for the apparent defect of Fus−/− HSCs. However, gene expression profiling identified changes in expression of several genes in Fus−/− HSCs, and dysregulated expression of some of these genes might be responsible for the defective function of Fus−/− HSCs. Disclosures: No relevant conflicts of interest to declare.

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Staege, Martin S., and Daniela Max. "Genetics and Epigenetics of the TET-ETS Translocation Network." Genetics & Epigenetics 2 (January 2009): GEG.S2815. http://dx.doi.org/10.4137/geg.s2815.

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In the present paper we review the translocation network involving TET and ETS family members with special focus on the Ewing family of tumors. FUS (fusion, involved in t(12;16) in malignant liposarcoma = TLS, Translocated in liposarcoma), EWSR1 (Ewing sarcoma breakpoint region 1) and TAF15 (TATA box-binding protein-associated factor, 68-KD) are the three human members of the TET family of RNA binding proteins. In addition, two EWSR1 pseudogenes are present in the human genome. TET family members are involved in several oncogenic gene fusions. Five of the 18 known fusion partners belong to the E26 (E twenty-six, ETS) family of transcription factors. Gene fusions between TET or ETS family members and other fusion partners link these gene fusions to a large network of oncogenic gene rearrangements.

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Reed, Damon R., Sant P. Chawla, Bhuvana Setty, Leo Mascarenhas, Paul A. Meyers, Jonathan Metts, Douglas James Harrison, et al. "Phase 1 expansion trial of the LSD1 inhibitor seclidemstat (SP-2577) with and without topotecan and cyclophosphamide (TC) in patients (pts) with relapsed or refractory Ewing sarcoma (ES) and select sarcomas." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): TPS11577. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps11577.

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TPS11577 Background: Several sarcomas possess chromosomal translocations in FET family members ( FUS, EWSR1, and TAF15) responsible for cancer development. Sarcomas caused by FET family gene rearrangements include ES, desmoplastic round cell small tumors (DSRCT), myxoid liposarcoma (ML), and several others. Lysine specific demethylase 1 (LSD1) is a critical protein for sarcoma development and progression through its colocalization and/or association with several FET family oncogenic transcription factors. This suggests that pharmacologic inhibition of LSD1 may be a therapeutic strategy. Seclidemstat (SP-2577, Salarius Pharmaceuticals) is an oral, first-in-class, small molecule with reversible, noncompetitive inhibition of LSD1 (IC50: 25–50 nM). In vitro and in vivo data demonstrate seclidemstat, or analogs, modulate EWS/ETS transcriptional activity, down-regulating oncogene expression and up-regulating tumor-suppressor gene expression, leading to significant tumor growth inhibition in ES mouse xenograft studies. Seclidemstat has shown in in vitro ES cell lines near additivity efficacy when added to TC. In in vitro studies of other FET-translocated sarcomas, including ML (FUS/DDIT3 fusion) and clear cell sarcoma (EWS/ATF1 fusion), seclidemstat showed anti-proliferative activity. In an ongoing Phase 1 trial investigating single agent seclidemstat in advanced solid tumors (NCT03895684), three pts with metastatic FET-translocated sarcomas had a median progression-free survival of 5.7 months (range: 4.3–7.2) with a best response of stable disease despite having a median of 5 (range: 1–7) prior therapies. Methods: This dose expansion Phase 1 study (NCT03600649) assesses seclidemstat at 900 mg PO BID, the recommended Phase 2 dose, in two expansion cohorts: a single agent expansion in select sarcoma pts (n = 30) and a safety lead-in dose escalation and expansion (n = 24) of seclidemstat combined with TC in pts with ES. Pts must be ≥12 years old, have ECOG performance status of 0 or 1, with a life expectancy > 4 months. In the select sarcoma cohort, pts must have ML (n = 15) or other sarcomas with FET family translocations (n = 15) including DSRCT. One to 3 prior lines of therapy are allowed. In the ES combination cohort, up to 2 lines of prior therapy are allowed. Primary objective is safety/tolerability and secondary objective is efficacy. The trial is currently recruiting across 8 locations in the United States. Clinical trial information: NCT03600649.

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Rojo, Rocio, Clare Pridans, David Langlais, and David A. Hume. "Transcriptional mechanisms that control expression of the macrophage colony-stimulating factor receptor locus." Clinical Science 131, no. 16 (July 31, 2017): 2161–82. http://dx.doi.org/10.1042/cs20170238.

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The proliferation, differentiation, and survival of cells of the macrophage lineage depends upon signals from the macrophage colony-stimulating factor (CSF) receptor (CSF1R). CSF1R is expressed by embryonic macrophages and induced early in adult hematopoiesis, upon commitment of multipotent progenitors to the myeloid lineage. Transcriptional activation of CSF1R requires interaction between members of the E26 transformation-specific family of transcription factors (Ets) (notably PU.1), C/EBP, RUNX, AP-1/ATF, interferon regulatory factor (IRF), STAT, KLF, REL, FUS/TLS (fused in sarcoma/ranslocated in liposarcoma) families, and conserved regulatory elements within the mouse and human CSF1R locus. One element, the Fms-intronic regulatory element (FIRE), within intron 2, is conserved functionally across all the amniotes. Lineage commitment in multipotent progenitors also requires down-regulation of specific transcription factors such as MYB, FLI1, basic leucine zipper transcriptional factor ATF-like (BATF3), GATA-1, and PAX5 that contribute to differentiation of alternative lineages and repress CSF1R transcription. Many of these transcription factors regulate each other, interact at the protein level, and are themselves downstream targets of CSF1R signaling. Control of CSF1R transcription involves feed–forward and feedback signaling in which CSF1R is both a target and a participant; and dysregulation of CSF1R expression and/or function is associated with numerous pathological conditions. In this review, we describe the regulatory network behind CSF1R expression during differentiation and development of cells of the mononuclear phagocyte system.

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Zou, Junhui, Anna Zielinska-Kwiatkowska, Michael L. Blackburn, Hitoshi Ichikawa, and Liu Yang. "Oncogenic TLS-ERG Fusion Protein Promotes Differentiation of Myeloid Progenitors into Myeloblasts but Blocks Their Terminal Differentiation." Blood 106, no. 11 (November 16, 2005): 1383. http://dx.doi.org/10.1182/blood.v106.11.1383.1383.

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Abstract In a subset of acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) in blast crisis, the TLS (translocation liposarcoma) gene is fused to the ERG (ets-related gene) gene through a recurrent t(16;21) translocation. This chromosomal translocation results in the generation of the TLS-ERG fusion protein. More recently, the same TLS-ERG fusion protein has also been identified in Ewing’s sarcoma in children. To investigate the oncogenic mechanism of TLS-ERG, we stably expressed TLS-ERG or its mutant TLS-ERGΔets in mouse L-G myeloid progenitor cells through retroviral transduction. L-G cells normally proliferate in the presence of IL-3 and undergo terminal differentiation into hypersegmented neutrophils when treated with G-CSF. In contrast, expression of TLS-ERG in L-G cells led to spontaneous differentiation into immature myeloblasts but G-CSF treatment of these cells failed to induce terminal differentiation. L-G myeloblasts harboring TLS-ERG were characterized by high levels of myeloperoxidase (MPO), a phenomenon also observed in immature myeloblasts isolated from human leukemia patients with the t(16;21) translocation. As deletion of the ets DNA-binding domain from TLS-ERG abolished its ability to promote spontaneous myeloblast differentiation or the ability to up-regulate the MPO gene, we further examined how TLS-ERG fusion protein might affect the functions of other regulators such as PU.1, an ets transcription factor known to play a critical role in the differentiation of myeloid progenitors. Though both proteins have similar DNA-binding property, TLS-ERG differs from PU.1 through binding directly to RNA polymerase II as well as through escaping repression by histone modification enzymes. Together, these findings suggest that the TLS-ERG fusion protein can cause blockage of myeloid differentiation by interfering with the gene expression program normally controlled by key regulators.

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Pan, Jing, Junhui Zou, Michael L. Blackburn, Marwan Yared, and Liu Yang. "TLS-ERG Fusion Protein Blocks Terminal Differentiation of Myeloid Progenitor Cells through Deregulation of Cyclin-Dependent Kinase 1 (CDK1)." Blood 108, no. 11 (November 16, 2006): 1441. http://dx.doi.org/10.1182/blood.v108.11.1441.1441.

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Abstract In a subset of acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) in blast crisis, the TLS (translocation liposarcoma) gene is fused to the ERG (ets-related gene) gene through a recurrent t(16;21) translocation. This chromosomal translocation results in the generation of TLS-ERG fusion protein. More recently, the same TLS-ERG fusion protein has also been identified in Ewing’s sarcoma in children. To investigate the oncogenic mechanism of TLS-ERG, we have stably expressed TLS-ERG in mouse L-G myeloid progenitor cells through retroviral transduction. L-G cells are dependent on IL-3 for proliferation and undergo terminal differentiation into mature neutrophils when treated with G-CSF. Retroviral expression of TLS-ERG fusion protein in L-G cells blocks G-CSF induced terminal differentiation and enables these cells to proliferate in the absence of IL-3. The ability to transform L-G myeloid progenitor cells appears to be an acquired function of the TLS-ERG fusion protein since neither wild-type TLS nor wild-type ERG is able to transform cells. The evolutionarily conserved arginine at position 367 within the ets domain of TLS-ERG is known to be critical to DNA binding, we therefore have replaced arginine at this position with a leucine (R367L). When stably expressed in L-G cells, this TLS-ERG mutant no longer possesses the ability to transform cells. As cellular transformation often reflects a robust cell cycle machinery, we have examined the effects of TLS-ERG on Cdk1, a major protein kinase involved in all four phases of the cell cycle. While the level of Cdk1 protein decreases to an undetectable level during G-CSF-induced terminal differentiation or after IL-3 withdrawal in control L-G cells harboring the empty retroviral vector, the level of Cdk1 protein remains unchanged in TLS-ERG cells following the same treatments. Through RT-PCR analysis, we have found that the steady state level of Cdk1 mRNA is not directly affected by TLS-ERG. Instead, our results show that TLS-ERG increases the stability of Cdk1 protein through repressing genes involved in protein degradation. Using a luciferase reporter construct, we have found that transcriptional repression by TLS-ERG can be reversed by 5-aza-2′-deoxycytidine (also called Decitabine, a DNA methyltransferase inhibitor) or by trichostatin A (a histone acetyltransferase inhibitor). Interestingly, treatment of TLS-ERG-expressing L-G cells with these two epigenetic drugs can also destabilize Cdk1 protein and facilitate terminal differentiation in these TLS-ERG cells. To investigate whether deregulation of Cdk1 protein is indeed correlated with oncogenic transformation by the TLS-ERG fusion protein, we have constructed a lentiviral vector for delivery of a dominant-negative form of Cdk1. In L-G cells harboring TLS-ERG, lentiviral expression of the dominant-negative Cdk1 is found to restore the ability of cells to undergo G-CSF-induced terminal differentiation. In addition, stable siRNA knockdown of Cdk1 is also able to release cells from TLS-ERG blockage of terminal differentiation. Together, these findings suggest that deregulation of Cdk1 activity by TLS-ERG fusion protein plays a critical role in cellular transformation in vitro, and the role of Cdk1 deregulation in leukemogenesis is currently being examined in vivo in a TLS-ERG mouse model.

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Yoneda, Ryoma, Shiho Suzuki, Tsukasa Mashima, Keiko Kondo, Takashi Nagata, Masato Katahira, and Riki Kurokawa. "The binding specificity of Translocated in LipoSarcoma/FUsed in Sarcoma with lncRNA transcribed from the promoter region of cyclin D1." Cell & Bioscience 6, no. 1 (January 25, 2016). http://dx.doi.org/10.1186/s13578-016-0068-8.

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Fujimoto, Kenta, and Riki Kurokawa. "Development of a mouse monoclonal antibody for the detection of asymmetric dimethylarginine of Translocated in LipoSarcoma/FUsed in Sarcoma and its application in analyzing methylated TLS." Cell & Bioscience 4, no. 1 (December 2014). http://dx.doi.org/10.1186/2045-3701-4-77.

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Harley, Jasmine, Cathleen Hagemann, Andrea Serio, and Rickie Patani. "TDP-43 and FUS mislocalization in VCP mutant motor neurons is reversed by pharmacological inhibition of the VCP D2 ATPase domain." Brain Communications 3, no. 3 (2021). http://dx.doi.org/10.1093/braincomms/fcab166.

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Abstract RNA binding proteins have been shown to play a key role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Mutations in valosin-containing protein (VCP/p97) cause ALS and exhibit the hallmark nuclear-to-cytoplasmic mislocalization of RNA binding proteins (RBPs). However, the mechanism by which mutations in VCP lead to this mislocalization of RBPs remains incompletely resolved. To address this, we used human-induced pluripotent stem cell-derived motor neurons carrying VCP mutations. We first demonstrate reduced nuclear-to-cytoplasmic ratios of transactive response DNA-binding protein 43 (TDP-43), fused in sarcoma/translocated in liposarcoma (FUS) and splicing factor proline and glutamine rich (SFPQ) in VCP mutant motor neurons. Upon closer analysis, we also find these RBPs are mislocalized to motor neuron neurites themselves. To address the hypothesis that altered function of the D2 ATPase domain of VCP causes RBP mislocalization, we used pharmacological inhibition of this domain in control motor neurons and found this does not recapitulate RBP mislocalization phenotypes. However, D2 domain inhibition in VCP mutant motor neurons was able to robustly reverse mislocalization of both TDP-43 and FUS, in addition to partially relocalizing SFPQ from the neurites. Together these results argue for a gain-of-function of D2 ATPase in VCP mutant human motor neurons driving the mislocalization of TDP-43 and FUS. Our data raise the intriguing possibility of harnessing VCP D2 ATPase inhibitors in the treatment of VCP-related ALS.

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Hamad, Nesreen, Ryoma Yoneda, Masatomo So, Riki Kurokawa, Takashi Nagata, and Masato Katahira. "Non-coding RNA suppresses FUS aggregation caused by mechanistic shear stress on pipetting in a sequence-dependent manner." Scientific Reports 11, no. 1 (May 4, 2021). http://dx.doi.org/10.1038/s41598-021-89075-w.

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AbstractFused in sarcoma/translocated in liposarcoma (FUS/TLS) is a multitasking RNA/DNA binding protein. FUS aggregation is implicated in various neurodegenerative diseases. RNA was suggested to modulate phase transition of FUS. Here, we found that FUS transforms into the amorphous aggregation state as an instant response to the shear stress caused by usual pipetting even at a low FUS concentration, 100 nM. It was revealed that non-coding RNA can suppress the transformation of FUS into aggregates. The suppressive effect of RNA on FUS aggregation is sequence-dependent. These results suggested that the non-coding RNA could be a prospective suppressor of FUS aggregation caused by mechanistic stress in cells. Our finding might pave the way for more research on the role of RNAs as aggregation inhibitors, which could facilitate the development of therapies for neurodegenerative diseases.

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Owen, Izzy, Debra Yee, Hala Wyne, Theodora Myrto Perdikari, Victoria Johnson, Jeremy Smyth, Robert Kortum, Nicolas L. Fawzi, and Frank Shewmaker. "The oncogenic transcription factor FUS-CHOP can undergo nuclear liquid–liquid phase separation." Journal of Cell Science 134, no. 17 (September 1, 2021). http://dx.doi.org/10.1242/jcs.258578.

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ABSTRACT Myxoid liposarcoma is caused by a chromosomal translocation resulting in a fusion protein comprised of the N terminus of FUS (fused in sarcoma) and the full-length transcription factor CHOP (CCAAT/enhancer-binding protein homologous protein, also known as DDIT3). FUS functions in RNA metabolism, and CHOP is a stress-induced transcription factor. The FUS-CHOP fusion protein causes unique gene expression and oncogenic transformation. Although it is clear that the FUS segment is required for oncogenic transformation, the mechanism of FUS-CHOP-induced transcriptional activation is unknown. Recently, some transcription factors and super enhancers have been proposed to undergo liquid–liquid phase separation and form membraneless compartments that recruit transcription machinery to gene promoters. Since phase separation of FUS depends on its N terminus, transcriptional activation by FUS-CHOP could result from the N terminus driving nuclear phase transitions. Here, we characterized FUS-CHOP in cells and in vitro, and observed novel phase-separating properties relative to unmodified CHOP. Our data indicate that FUS-CHOP forms phase-separated condensates that colocalize with BRD4, a marker of super enhancer condensates. We provide evidence that the FUS-CHOP phase transition is a novel oncogenic mechanism and potential therapeutic target for myxoid liposarcoma. This article has an associated First Person interview with the first author of the paper.

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Journal articles on the topic 'Fused in Sarcoma/Translocated in Liposarcoma'

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