Journal articles: 'Translocated in Liposarcoma'

1

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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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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Sánchez-Ramos, Cristina, Alberto Tierrez, Oscar Fabregat-Andrés, Brigitte Wild, Fatima Sánchez-Cabo, Alessandro Arduini, Ana Dopazo, and María Monsalve. "PGC-1α Regulates Translocated in Liposarcoma Activity: Role in Oxidative Stress Gene Expression." Antioxidants & Redox Signaling 15, no. 2 (July 15, 2011): 325–37. http://dx.doi.org/10.1089/ars.2010.3643.

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4

Klint, Peter, Ulf Hellman, Christer Wernstedt, Pierre Åman, David Ron, and Lena Claesson-Welsh. "Translocated in liposarcoma (TLS) is a substrate for fibroblast growth factor receptor-1." Cellular Signalling 16, no. 4 (April 2004): 515–20. http://dx.doi.org/10.1016/j.cellsig.2003.09.007.

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5

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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Powers, C. Andrew, Mukul Mathur, Bruce M. Raaka, David Ron, and Herbert H. Samuels. "TLS (Translocated-in-Liposarcoma) Is a High-Affinity Interactor for Steroid, Thyroid Hormone, and Retinoid Receptors." Molecular Endocrinology 12, no. 1 (January 1, 1998): 4–18. http://dx.doi.org/10.1210/mend.12.1.0043.

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7

Sugiura, Tomohito, Shuji Matsuda, Satoshi Kurosaka, Nobuhiro Nakai, Keita Fukumoto, Tetsuya Takahashi, Hirofumi Maruyama, Kazunori Imaizumi, Masayasu Matsumoto, and Toru Takumi. "Translocated in liposarcoma regulates the distribution and function of mammalian enabled, a modulator of actin dynamics." FEBS Journal 283, no. 8 (March 2, 2016): 1475–87. http://dx.doi.org/10.1111/febs.13685.

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Powers, C. A. "TLS (Translocated-in-Liposarcoma) Is a High-Affinity Interactor for Steroid, Thyroid Hormone, and Retinoid Receptors." Molecular Endocrinology 12, no. 1 (January 1, 1997): 4–18. http://dx.doi.org/10.1210/me.12.1.4.

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9

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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10

Uranishi, Hiroaki, Toshifumi Tetsuka, Mayumi Yamashita, Kaori Asamitsu, Manabu Shimizu, Makoto Itoh, and Takashi Okamoto. "Involvement of the Pro-oncoprotein TLS (Translocated in Liposarcoma) in Nuclear Factor-κB p65-mediated Transcription as a Coactivator." Journal of Biological Chemistry 276, no. 16 (January 24, 2001): 13395–401. http://dx.doi.org/10.1074/jbc.m011176200.

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11

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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12

Cui, Wei, Ryoma Yoneda, Naomi Ueda, and Riki Kurokawa. "Arginine methylation of translocated in liposarcoma (TLS) inhibits its binding to long noncoding RNA, abrogating TLS-mediated repression of CBP/p300 activity." Journal of Biological Chemistry 293, no. 28 (May 21, 2018): 10937–48. http://dx.doi.org/10.1074/jbc.ra117.000598.

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13

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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14

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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15

Tan, Adelene Y., and James L. Manley. "TLS Inhibits RNA Polymerase III Transcription." Molecular and Cellular Biology 30, no. 1 (October 19, 2009): 186–96. http://dx.doi.org/10.1128/mcb.00884-09.

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ABSTRACT RNA transcription by all the three RNA polymerases (RNAPs) is tightly controlled, and loss of regulation can lead to, for example, cellular transformation and cancer. While most transcription factors act specifically with one polymerase, a small number have been shown to affect more than one polymerase to coordinate overall levels of transcription in cells. Here we show that TLS (translocated in liposarcoma), a protein originally identified as the product of a chromosomal translocation and which associates with both RNAP II and the spliceosome, also represses transcription by RNAP III. TLS was found to repress transcription from all three classes of RNAP III promoters in vitro and to associate with RNAP III genes in vivo, perhaps via a direct interaction with the pan-specific transcription factor TATA-binding protein (TBP). Depletion of TLS by small interfering RNA (siRNA) in HeLa cells resulted in increased steady-state levels of RNAP III transcripts as well as increased RNAP III and TBP occupancy at RNAP III-transcribed genes. Conversely, overexpression of TLS decreased accumulation of RNAP III transcripts. These unexpected findings indicate that TLS regulates both RNAPs II and III and supports the possibility that cross-regulation between RNA polymerases is important in maintaining normal cell growth.

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16

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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17

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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18

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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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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20

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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21

Sugawara, Takeaki, and Atsushi Iwama. "Impaired Repopulating Activity of Fus-Deficient Hematopoietic Stem Cells." Blood 110, no. 11 (November 16, 2007): 2222. http://dx.doi.org/10.1182/blood.v110.11.2222.2222.

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Abstract RNA-binding protein FUS (also known as TLS) was originally identified in chromosomal translocation in human myxoid liposarcoma. The FUS gene is also translocated with the transcription factor gene ERG in human myeloid leukemia with recurrent chromosomal translocation t(16;21). Multiple data suggest that wild-type FUS is also involved in the development of leukemia as one of the downstream targets for oncoproteins including BCR-ABL. However, little is known about the role of FUS in the normal hematopoiesis. The previous report demonstrated that Fus-deficient (Fus−/−) newborn mice, which die shortly after birth because they cannot suckle, have a non-cell-autonomous defect in B lymphocyte development. No cell-autonomous defect of Fus−/− hematopoietic cells has been documented. Here we report the detailed analyses of the Fus−/− fetal liver hematopoietic stem cells (HSCs). Fus−/− fetal livers at embryonic day 14.5 were smaller in size and exhibited a significant reduction in hematopoietic cell numbers by 60% compared with the wild type (WT). Nonetheless, no significant difference was observed in the proportion of stem/progenitor cell fraction (lineage-marker-c-Kit+Sca-1+; KSL) as well as colony-forming cells between WT and Fus−/− fetal livers. Fus−/− KSL cells proliferated and differentiated almost normally in vitro. To examine in vivo repopulating activity, we transplanted fetal liver cells to lethally irradiated CD45.1 recipients with competitor bone marrow cells. Fus−/− fetal liver donor cells reconstituted recipients’ hematopoiesis for the long term and contributed to all cell lineages including B lymphocytes. In contrast to the in vitro results, however, the chimerism of donor-derived cells was significantly lower in recipients receiving Fus−/− fetal liver cells compared with WT controls (approximately 2-fold reduction). This trend was reproducible with both unfractionated and purified KSL fetal liver test cells. Our data demonstrated that the proto-oncogene Fus is involved in the maintenance of normal HSC functions. Detailed analyses on the underlying mechanisms are in progress.

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22

Zinszner, H., J. Sok, D. Immanuel, Y. Yin, and D. Ron. "TLS (FUS) binds RNA in vivo and engages in nucleo-cytoplasmic shuttling." Journal of Cell Science 110, no. 15 (August 1, 1997): 1741–50. http://dx.doi.org/10.1242/jcs.110.15.1741.

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TLS, the product of a gene commonly translocated in liposarcomas (TLS), is prototypical of a newly identified class of nuclear proteins that contain a C-terminal domain with a distinct RNA recognition motif (RRM) surrounded by Arg-Gly-Gly (RGG) repeats. Its unique N terminus serves as an essential transforming domain for a number of fusion oncoproteins in human sarcomas and leukemias. In this study we use an in vivo UV crosslinking procedure to probe the interactions of TLS with RNA. TLS is found to bind RNA in vivo and the association of TLS with RNA is rapidly diminished by treating cells with transcriptional inhibitors. This suggests that the species bound by TLS turns over rapidly. Surprisingly, the RRM was found to be dispensable for RNA binding by TLS in vivo, suggesting that at any one time most of the interactions between TLS and RNA in the cell are not sequence specific. Analysis of inter specific heterokaryons formed between human and mouse or Xenopus cells revealed that TLS engages in rapid nucleocytoplasmic shuttling, a finding confirmed by the ability of anti-TLS antibodies to trap TLS when injected into the cytoplasm of HeLa cells. Cellular fractionation experiments suggest that TLS binds to RNA in both the nucleus and cytoplasm and support the hypothesis that TLS functions as a heterogeneous ribonuclear protein (hnRNP)-like chaperone of RNA. These findings are discussed in the context of the role altered forms of TLS play in cellular transformation.

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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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24

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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25

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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26

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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Journal articles on the topic 'Translocated in Liposarcoma'

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