Ewing sarcoma gene Ews regulates hematopoietic stem cell senescence

Cho, Joonseok; Shen, Hongmei; Yu, Hui; Li, Hongjie; Cheng, Tao; Lee, Sean Bong; Lee, Byeong Chel

doi:10.1182/blood-2010-04-279349

Cited by 43 publications

(38 citation statements)

References 50 publications

(59 reference statements)

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“…3,8 EWS fusion proteins, such as FLI1, 1 or EWS interaction partners, such as CBP, 3 can control the transcription of mRNA of many genes. It has been previously demonstrated that EWS is part of the Drosha/ DGCR complex, but the potential roles for EWS in miRNA biogenesis or regulation has not been examined.…”

Section: Discussionmentioning

confidence: 99%

A multifunctional protein EWS regulates the expression of Drosha and microRNAs

et al. 2013

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, 5,6,9 EWS (Ewing's Sarcoma) gene encodes an RNA/DNA-binding protein that is ubiquitously expressed and involved in various cellular processes. EWS deficiency leads to impaired development and early senescence through unknown mechanisms. We found that EWS regulates the expression of Drosha and microRNAs (miRNAs). EWS deficiency resulted in increased expression of Drosha, a well-known microprocessor, and increased levels of miR-29b and miR-18b. Importantly, miR-29b and miR-18b were directly involved in the post-transcriptional regulation of collagen IV alpha 1 (Col4a1) and connective tissue growth factor (CTGF) in EWS knock-out (KO) mouse embryonic fibroblast cells. The upregulation of Drosha, miR-29b and miR-18b and the sequential downregulation of Col4a1 and CTGF contributed to the deregulation of dermal development in EWS KO mice. Otherwise, knockdown of Drosha rescued miRNA-dependent downregulation of Col4a1 and CTGF proteins. Taken together, our data indicate that EWS is involved in post-transcriptional regulation of Col4a1 and CTGF via a Drosha-miRNA-dependent pathway. This finding suggests that EWS has a novel role in dermal morphogenesis through the modulation of miRNA biogenesis. 1 EWS also interacts with subunits of transcription factor II D, CREB-binding protein (CBP) and RNA polymerase II complexes, suggesting a role in basic transcription.2 Subsequent studies have shown that EWS acts as a transcriptional activator for BRN3A, HNF3, and OCT4 in a cell-type-and promoter-specific manner.3-5 Interestingly, EWS gene is frequently rearranged by chromosomal translocations in several cancers, leading to its fusion with many transcription factors including FLI1, ATF1, and WT1. The resulting chimeric fusion proteins, such as EWS-FLI1, EWS-ATF1, and EWS-WT1, function as aberrant transcription factors that drive proliferation, survival, and transformation.

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Section: Discussionmentioning

confidence: 99%

A multifunctional protein EWS regulates the expression of Drosha and microRNAs

et al. 2013

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“…EWS encodes an RNA/ssDNA-binding protein that plays multiple roles in diverse cellular processes, such as maturation of pre-B lymphocytes, meiosis, hypersensitivity to DNA damage, prevention of premature senescence of fibroblasts (6), and hematopoietic stem cells (7), mitosis (8), cell-fate determination of classical brown fat (9), regulation of microRNAs (10), and regulation of genotoxic-induced alternative splicing (11,12). The NTD of EWS contains multiple degenerate repeats of the SYGQQS motif that functions as a potent transcriptional activation domain (13,14).…”

Section: Introductionmentioning

confidence: 99%

EWS–WT1 Oncoprotein Activates Neuronal Reprogramming Factor ASCL1 and Promotes Neural Differentiation

et al. 2014

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The oncogenic fusion gene EWS-WT1 is the defining chromosomal translocation in desmoplastic small roundcell tumors (DSRCT), a rare but aggressive soft tissue sarcoma with a high rate of mortality. EWS-WT1 functions as an aberrant transcription factor that drives tumorigenesis, but the mechanistic basis for its pathogenic activity is not well understood. To address this question, we created a transgenic mouse strain that permits physiologic expression of EWS-WT1 under the native murine Ews promoter. EWS-WT1 expression led to a dramatic induction of many neuronal genes in embryonic fibroblasts and primary DSRCT, most notably the neural reprogramming factor ASCL1. Mechanistic analyses demonstrated that EWS-WT1 directly bound the proximal promoter of ASCL1, activating its transcription through multiple WT1-responsive elements. Conversely, EWS-WT1 silencing in DSRCT cells reduced ASCL1 expression and cell viability. Notably, exposure of DSRCT cells to neuronal induction media increased neural gene expression and induced neurite-like projections, both of which were abrogated by silencing EWS-WT1. Taken together, our findings reveal that EWS-WT1 can activate neural gene expression and direct partial neural differentiation via ASCL1, suggesting agents that promote neural differentiation might offer a novel therapeutic approach to treat DSRCT. Cancer Res; 74(16); 4526-35. Ó2014 AACR.

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“…EWS is a multifunctional protein with multiple roles in diverse cellular processes, such as maturation of pre B lymphocytes, meiosis, hypersensitivity to DNA damage, prevention of premature senescence of fibroblasts (11) and hematopoietic stem cells (12), mitosis (13), DNA damage-induced alternative splicing (9, 10), cell-fate determination of classical brown fat (8) and regulation of microRNAs (15). This study ascribes a new function to EWS in mitochondrial homeostasis and cellular energy metabolism.…”

Section: Discussionmentioning

confidence: 96%

“…EWS is also involved in alternative splicing of specific genes in response to DNA damage (9,10). Animal studies with genetic ablation of Ews have revealed a surprisingly diverse role of EWS in various cellular processes such as pre-B lymphocyte development, meiosis, mitosis and prevention of premature cellular senescence in fibroblasts and hematopoietic stem cells (11)(12)(13). Recently, it was shown that EWS is required for determining embryonic brown fat cell fate during development (8), for in vitro white fat differentiation (14), and in the regulation of microRNAs (15).…”

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confidence: 99%

Inactivation of EWS reduces PGC-1α protein stability and mitochondrial homeostasis

Park

Kang

Lee

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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EWS (Ewing sarcoma) encodes an RNA/ssDNA binding protein that is frequently rearranged in a number of different cancers by chromosomal translocations. Physiologically, EWS has diverse and essential roles in various organ development and cellular processes. In this study, we uncovered a new role of EWS in mitochondrial homeostasis and energy metabolism. Loss of EWS leads to a significant decrease in mitochondria abundance and activity, which is caused by a rapid degradation of Peroxisome proliferator-activated receptor γ Coactivator (PGC-1α), a central regulator of mitochondria biogenesis, function, and cellular energy metabolism. EWS inactivation leads to increased ubiquitination and proteolysis of PGC-1α via proteasome pathway. Complementation of EWS in Ews-deficient cells restores PGC-1α and mitochondrial abundance. We found that expression of E3 ubiquitin ligase, FBXW7 (F-box/WD40 domain protein 7), is increased in the absence of Ews and depletion of Fbxw7 in Ews-null cells restores PGC-1α expression and mitochondrial density. Consistent with these findings, mitochondrial abundance and activity are significantly reduced in brown fat and skeletal muscles of Ews-deficient mice. Furthermore, expression of mitochondrial biogenesis, respiration and fatty acid β-oxidation genes is significantly reduced in the liver of Ews-null mice. These results demonstrate a novel role of EWS in mitochondrial and cellular energy homeostasis by controlling PGC-1α protein stability, and further implicate altered mitochondrial and energy metabolism in cancers harboring the EWS translocation.EWS | PGC-1alpha | protein stability | mitochondria homeostasis | energy metabolism E wing sarcoma breakpoint region 1 (EWSR1, herein termed EWS) was first identified from the Ewing sarcoma chromosomal breakpoint t(11, 22)(q24;q12) region as a translocationgenerated fusion gene between EWS and FLI1 (Friend leukemia integration 1) (1), an ETS-family of transcription factor. EWS is a member of the FET (or TET) family of RNA and ssDNAbinding proteins, which includes two other members, FUS/TLS (Fused in Sarcoma/Translocated in Liposarcoma) and TAF15/ hTAFII68 (TATA-binding protein-associated factor 15/human TATA-binding protein-associated factor II 68) as well as a Drosophila protein, Cabeza/SARFH (1, 2). A transcriptional role of EWS has been inferred by its association with basic transcription factors (3, 4) and by its modulation of several transcription factor activities (5-8). EWS is also involved in alternative splicing of specific genes in response to DNA damage (9, 10). Animal studies with genetic ablation of Ews have revealed a surprisingly diverse role of EWS in various cellular processes such as pre-B lymphocyte development, meiosis, mitosis and prevention of premature cellular senescence in fibroblasts and hematopoietic stem cells (11-13). Recently, it was shown that EWS is required for determining embryonic brown fat cell fate during development (8), for in vitro white fat differentiation (14), and in the regulation of microRNAs (15).The ...

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Ewing sarcoma gene Ews regulates hematopoietic stem cell senescence

Cited by 43 publications

References 50 publications

A multifunctional protein EWS regulates the expression of Drosha and microRNAs

A multifunctional protein EWS regulates the expression of Drosha and microRNAs

EWS–WT1 Oncoprotein Activates Neuronal Reprogramming Factor ASCL1 and Promotes Neural Differentiation

Inactivation of EWS reduces PGC-1α protein stability and mitochondrial homeostasis

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