Disease relevance of FUS

• The FUS gene at 16p11 fuses with DDIT3 and ATF1 as the result of translocations with chromosome band 12q13 in myxoid liposarcoma and angiomatoid fibrous histiocytoma, respectively, and with ERG as the result of a t(16;21)(p11;q22) in acute myeloid leukemia [1].
• We here show that a t(7;16)(q33;p11) in two cases of low grade fibromyxoid sarcoma fuses the FUS gene to BBF2H7, a previously uncharacterized gene that is homologous to the Drosophila Bbf-2 gene [1].
• TLS/FUS is a nucleic acid-binding protein whose N-terminal half functions as a transcriptional activator domain in fusion oncoproteins found in human leukemias and liposarcomas [2] [3].
• In order to investigate the downstream targets of DDIT3, and the transforming effects of the FUS-DDIT3 fusion protein, we have introduced DDIT3-GFP and FUS-DDIT3-GFP constructs into a human fibrosarcoma cell line [4].
• An RNA-binding protein gene, TLS/FUS, is fused to ERG in human myeloid leukemia with t(16;21) chromosomal translocation [5] [2].

Psychiatry related information on FUS

• RESULTS: Results show that the TLS decreases reaction time (p = 0.001) and movement time (p = 0.001) for simulated subject (astronaut) motion around the ISS [6].
• Immunohistochemistry showed that TLS was associated with neuronal intranuclear inclusions of Huntington disease human brain [7].

High impact information on FUS

• FUS resembles a transcription factor in that it binds DNA, contributes a transcriptional activation domain to the FUS-ERG oncoprotein and interacts with several transcription factors in vitro [2] [8] [9].
• Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma [10].
• We show that the translocation t(12;16)(q13:p11) in malignant myxoid liposarcoma can be a fusion of the CHOP dominant negative transcription factor gene with a novel gene, FUS, which can result in fusion of the FUS glycine-rich protein with the whole CHOP coding region [10].
• TLS is a novel nuclear RNA-binding protein with extensive sequence similarity to EWS, the product of a gene commonly translocated in Ewing's sarcoma [11] [2].
• In TLS-CHOP the RNA-binding domain of TLS is replaced by the DNA-binding and leucine zipper dimerization domain of CHOP [11].

Chemical compound and disease context of FUS

• One case of squamous cell carcinoma was called high grade squamous intraepithelial lesion (HGSIL) on TLS while the CS was unsatisfactory [12].
• Eleven patients with hyperplasia of the lingual tonsil were treated with a Tungsram TLS 61 CO2 laser coupled to an operating microscope [13].
• We reviewed the data of 26 children with malignancy at risk for TLS who received rasburicase for treatment or prophylaxis of acute hyperuricemia, producing a significant decrease in uric acid level in all the patients [14].

Biological context of FUS

• The gene encoding the human TLS protein, also termed FUS, is located at the site of chromosomal translocations in human leukemias and sarcomas where it forms a chimeric fusion gene with one of several different genes [2] [15].
• Exon 3 of FUS corresponds to exons 3 and 4 in EWS [16].
• Oncoprotein TLS interacts with serine-arginine proteins involved in RNA splicing [15].
• To identify interacting partners of TLS, we screened a yeast two-hybrid cDNA library constructed from mouse hematopoietic cells using the C-terminal region of TLS in the bait plasmid [15].
• Encoding a protein with a putative coiled-coil structure, TFG previously was identified by a homology search in the Expressed Sequence Tag Database as having an SPYGQ-rich region similar to the N-terminal parts of EWS and TLS [17].

Anatomical context of FUS

• Our results suggest that the matrix protein TLS/FUS plays a role in spliceosome assembly [3].
• No or little variation in FUS or EWS expression was seen when resting lymphocytes were activated [16].
• Here we report the association of TLS/FUS with the nuclear matrix and investigate its role in splicing [3].
• Expression of the FUS-CHOP fusion protein in primary mesenchymal progenitor cells gives rise to a model of myxoid liposarcoma [18].
• The expression of FUS/TLS was closely associated with the accumulation of beta-catenin and with the undifferentiated status of intestinal epithelial cells [19].

Associations of FUS with chemical compounds

• The N-terminal half of TLS bound to thyroid hormone receptor with high affinity while the receptor was bound to appropriate DNA target sites [20].
• TLS (translocated-in-liposarcoma) is a high-affinity interactor for steroid, thyroid hormone, and retinoid receptors [20].
• As a consequence the normally nontranslated exon 2 is translated and in both types there is in the junction between FUS and CHOP a shift from a FUS glycine codon to a valine codon in the chimeric mRNA [21].
• DNA annealing and D-loop formation catalyzed by hPOMp75/TLS require Mg(2+) and are ATP-independent [22].
• Moreover, induction of differentiation of mouse F9 line by retinoic acid leads to the inhibition of both POMp100 and TLS/POMp75 activities [23].

Physical interactions of FUS

• The TLS-CHOP oncoprotein, found in the majority of human myxoid liposarcomas, consists of a fusion between the transcription factor CHOP/GADD153 and the N terminus of an RNA-binding protein TLS/FUS [24].
• The liposarcoma fusion protein TLS/CHOP retains the ability to bind RNA Pol II but lacks the ability to recruit YB-1 due to replacement of the C-terminal domain of TLS by CHOP [25].
• The TLS/FUS gene has been identified as a translocated gene in myxoid liposarcoma by the t(12;16)(q13;p11) translocation and encodes an RNA-binding protein that is highly homologous to the product of the EWS gene involved in Ewing's sarcoma [5].
• beta-catenin interacts with the FUS proto-oncogene product and regulates pre-mRNA splicing [19].
• The translocation results in rearrangements of the CHOP gene in 12q13 and the FUS gene in 16p11, creating a fusion gene where the RNA-binding domain of FUS is replaced by the DNA-binding and leucine zipper dimerization domain of CHOP [21].

Regulatory relationships of FUS

• RNA splicing mediated by YB-1 is inhibited by TLS/CHOP in human myxoid liposarcoma cells [25].
• Expression of FUS is suggested to provide growth-promoting activity to myeloid cells similar to the activity of hematopoietic cytokine receptors [26].

Other interactions of FUS

• TLS, EWS and TAF15: a model for transcriptional integration of gene expression [27].
• The interaction between TLS and the stress-response protein YB-1 is an example of how these proteins can induce a multi-faceted change in gene expression, as they can interact to induce changes in both transcription and splicing of target genes [27].
• Most MLS/RCLS carry a t(12;16) translocation, resulting in a FUS-DDIT3 fusion gene [28].
• The FUS gene is rearranged in the t(12;16)(q13;p11) that characterizes myxoid liposarcoma and in acute myeloid leukemia with t(16;21)(p11;q22), while the ATF-1 gene is rearranged in the t(12;22)(q13;q12) found recurrently in clear cell sarcomas (malignant melanoma of soft parts) [29].
• The interaction between TLS/FUS and ZNF198 was confirmed using Western blot analysis [30].

Analytical, diagnostic and therapeutic context of FUS

• In addition, the effect of DDIT3 and FUS-DDIT3 on the expression of other acute phase genes was examined using real-time PCR [4].
• The interactions between TLS and these two SR proteins were confirmed by co-transfection and immunoprecipitation studies [15].
• Sequence analysis revealed caz is related to two human genes, EWS and TLS, which are involved in chromosomal translocations [31].
• In the two other t(16;21)-positive Ewing's cases, we performed bacterial artificial chromosome fluorescence in situ hybridization analysis on metaphases and interphase nuclei to demonstrate colocalization of bacterial artificial chromosomes containing FUS and ERG genes, also highly suggestive of fusion gene formation [32].
• Comparison of POM activity of TLS/FUS with the amount of TLS protein detected by Western blot, suggests that the POM activity could be regulated by post-translation modification [23].

References