The Experts below are selected from a list of 210 Experts worldwide ranked by ideXlab platform
Josiane E. Eid - One of the best experts on this subject based on the ideXlab platform.
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The Synovial Sarcoma-Associated SYT-SSX2 Oncogene Antagonizes the Polycomb Complex Protein Bmi1
PloS one, 2009Co-Authors: Roy Barco, Christina B. Garcia, Josiane E. EidAbstract:This study demonstrates deregulation of polycomb activity by the synovial sarcoma-associated SYT-SSX2 oncogene, also known as SS18-SSX2. Synovial sarcoma is a Soft Tissue Cancer associated with a recurrent t(X:18) translocation event that generates one of two fusion proteins, SYT-SSX1 or SYT-SSX2. The role of the translocation products in this disease is poorly understood. We present evidence that the SYT-SSX2 fusion protein interacts with the polycomb repressive complex and modulates its gene silencing activity. SYT-SSX2 causes destabilization of the polycomb subunit Bmi1, resulting in impairment of polycomb-associated histone H2A ubiquitination and reactivation of polycomb target genes. Silencing by polycomb complexes plays a vital role in numerous physiological processes. In recent years, numerous reports have implicated gain of polycomb silencing function in several Cancers. This study provides evidence that, in the appropriate context, expression of the SYT-SSX2 oncogene leads to loss of polycomb function. It challenges the notion that Cancer is solely associated with an increase in polycomb function and suggests that any imbalance in polycomb activity could drive the cell toward oncogenesis. These findings provide a mechanism by which the SYT-SSX2 chimera may contribute to synovial sarcoma pathogenesis.
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The synovial sarcoma SYT-SSX2 oncogene remodels the cytoskeleton through activation of the ephrin pathway.
Molecular biology of the cell, 2007Co-Authors: Roy Barco, Christina B. Garcia, Laura B. Hunt, Andrea L. Frump, Andrew E. Benesh, Robert L. Caldwell, Josiane E. EidAbstract:Synovial sarcoma is a Soft Tissue Cancer associated with a recurrent t(X:18) translocation that generates one of two fusion proteins, SYT-SSX1 or SYT-SSX2. In this study, we demonstrate that SYT-SSX2 is a unique oncogene. Rather than confer enhanced proliferation on its target cells, SYT-SSX2 instead causes a profound alteration of their architecture. This aberrant morphology included elongation of the cell body and formation of neurite-like extensions. We also observed that cells transduced with SYT-SSX2 often repulsed one another. Notably, cell repulsion is a known component of ephrin signaling. Further analysis of SYT-SSX2–infected cells revealed significant increases in the expression and activation of Eph/ephrin pathway components. On blockade of EphB2 signaling SYT-SSX2 infectants demonstrated significant reversion of the aberrant cytoskeletal phenotype. In addition, we discovered, in parallel, that SYT-SSX2 induced stabilization of the microtubule network accompanied by accumulation of detyrosinated Glu tubulin and nocodazole resistance. Glu tubulin regulation was independent of ephrin signaling. The clinical relevance of these studies was confirmed by abundant expression of both EphB2 and Glu tubulin in SYT-SSX2–positive synovial sarcoma Tissues. These results indicate that SYT-SSX2 exerts part of its oncogenic effect by altering cytoskeletal architecture in an Eph-dependent manner and cytoskeletal stability through a concurrent and distinct pathway.
Christina B. Garcia - One of the best experts on this subject based on the ideXlab platform.
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Targeting the Wnt Pathway in Synovial Sarcoma Models
Cancer discovery, 2013Co-Authors: Whitney Barham, Christina B. Garcia, Andrea L. Frump, Taylor P. Sherrill, Kenyi Saito-diaz, Michael N. Vansaun, Barbara Fingleton, Linda A. Gleaves, Darren Orton, Mario R. CapecchiAbstract:Synovial sarcoma is an aggressive Soft-Tissue malignancy of children and young adults, with no effective systemic therapies. Its specific oncogene, SYT-SSX (SS18-SSX), drives sarcoma initiation and development. The exact mechanism of SYT-SSX oncogenic function remains unknown. In an SYT-SSX2 transgenic model, we show that a constitutive Wnt/β-catenin signal is aberrantly activated by SYT-SSX2, and inhibition of Wnt signaling through the genetic loss of β-catenin blocks synovial sarcoma tumor formation. In a combination of cell-based and synovial sarcoma tumor xenograft models, we show that inhibition of the Wnt cascade through coreceptor blockade and the use of small-molecule CK1α activators arrests synovial sarcoma tumor growth. We find that upregulation of the Wnt/β-catenin cascade by SYT-SSX2 correlates with its nuclear reprogramming function. These studies reveal the central role of Wnt/β-catenin signaling in SYT-SSX2-induced sarcoma genesis, and open new venues for the development of effective synovial sarcoma curative agents. Synovial sarcoma is an aggressive Soft-Tissue Cancer that afflicts children and young adults, and for which there is no effective treatment. The current studies provide critical insight into our understanding of the pathogenesis of SYT–SSX-dependent synovial sarcoma and pave the way for the development of effective therapeutic agents for the treatment of the disease in humans. ©2013 AACR.
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The Synovial Sarcoma-Associated SYT-SSX2 Oncogene Antagonizes the Polycomb Complex Protein Bmi1
PloS one, 2009Co-Authors: Roy Barco, Christina B. Garcia, Josiane E. EidAbstract:This study demonstrates deregulation of polycomb activity by the synovial sarcoma-associated SYT-SSX2 oncogene, also known as SS18-SSX2. Synovial sarcoma is a Soft Tissue Cancer associated with a recurrent t(X:18) translocation event that generates one of two fusion proteins, SYT-SSX1 or SYT-SSX2. The role of the translocation products in this disease is poorly understood. We present evidence that the SYT-SSX2 fusion protein interacts with the polycomb repressive complex and modulates its gene silencing activity. SYT-SSX2 causes destabilization of the polycomb subunit Bmi1, resulting in impairment of polycomb-associated histone H2A ubiquitination and reactivation of polycomb target genes. Silencing by polycomb complexes plays a vital role in numerous physiological processes. In recent years, numerous reports have implicated gain of polycomb silencing function in several Cancers. This study provides evidence that, in the appropriate context, expression of the SYT-SSX2 oncogene leads to loss of polycomb function. It challenges the notion that Cancer is solely associated with an increase in polycomb function and suggests that any imbalance in polycomb activity could drive the cell toward oncogenesis. These findings provide a mechanism by which the SYT-SSX2 chimera may contribute to synovial sarcoma pathogenesis.
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The synovial sarcoma SYT-SSX2 oncogene remodels the cytoskeleton through activation of the ephrin pathway.
Molecular biology of the cell, 2007Co-Authors: Roy Barco, Christina B. Garcia, Laura B. Hunt, Andrea L. Frump, Andrew E. Benesh, Robert L. Caldwell, Josiane E. EidAbstract:Synovial sarcoma is a Soft Tissue Cancer associated with a recurrent t(X:18) translocation that generates one of two fusion proteins, SYT-SSX1 or SYT-SSX2. In this study, we demonstrate that SYT-SSX2 is a unique oncogene. Rather than confer enhanced proliferation on its target cells, SYT-SSX2 instead causes a profound alteration of their architecture. This aberrant morphology included elongation of the cell body and formation of neurite-like extensions. We also observed that cells transduced with SYT-SSX2 often repulsed one another. Notably, cell repulsion is a known component of ephrin signaling. Further analysis of SYT-SSX2–infected cells revealed significant increases in the expression and activation of Eph/ephrin pathway components. On blockade of EphB2 signaling SYT-SSX2 infectants demonstrated significant reversion of the aberrant cytoskeletal phenotype. In addition, we discovered, in parallel, that SYT-SSX2 induced stabilization of the microtubule network accompanied by accumulation of detyrosinated Glu tubulin and nocodazole resistance. Glu tubulin regulation was independent of ephrin signaling. The clinical relevance of these studies was confirmed by abundant expression of both EphB2 and Glu tubulin in SYT-SSX2–positive synovial sarcoma Tissues. These results indicate that SYT-SSX2 exerts part of its oncogenic effect by altering cytoskeletal architecture in an Eph-dependent manner and cytoskeletal stability through a concurrent and distinct pathway.
Roy Barco - One of the best experts on this subject based on the ideXlab platform.
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The Synovial Sarcoma-Associated SYT-SSX2 Oncogene Antagonizes the Polycomb Complex Protein Bmi1
PloS one, 2009Co-Authors: Roy Barco, Christina B. Garcia, Josiane E. EidAbstract:This study demonstrates deregulation of polycomb activity by the synovial sarcoma-associated SYT-SSX2 oncogene, also known as SS18-SSX2. Synovial sarcoma is a Soft Tissue Cancer associated with a recurrent t(X:18) translocation event that generates one of two fusion proteins, SYT-SSX1 or SYT-SSX2. The role of the translocation products in this disease is poorly understood. We present evidence that the SYT-SSX2 fusion protein interacts with the polycomb repressive complex and modulates its gene silencing activity. SYT-SSX2 causes destabilization of the polycomb subunit Bmi1, resulting in impairment of polycomb-associated histone H2A ubiquitination and reactivation of polycomb target genes. Silencing by polycomb complexes plays a vital role in numerous physiological processes. In recent years, numerous reports have implicated gain of polycomb silencing function in several Cancers. This study provides evidence that, in the appropriate context, expression of the SYT-SSX2 oncogene leads to loss of polycomb function. It challenges the notion that Cancer is solely associated with an increase in polycomb function and suggests that any imbalance in polycomb activity could drive the cell toward oncogenesis. These findings provide a mechanism by which the SYT-SSX2 chimera may contribute to synovial sarcoma pathogenesis.
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The synovial sarcoma SYT-SSX2 oncogene remodels the cytoskeleton through activation of the ephrin pathway.
Molecular biology of the cell, 2007Co-Authors: Roy Barco, Christina B. Garcia, Laura B. Hunt, Andrea L. Frump, Andrew E. Benesh, Robert L. Caldwell, Josiane E. EidAbstract:Synovial sarcoma is a Soft Tissue Cancer associated with a recurrent t(X:18) translocation that generates one of two fusion proteins, SYT-SSX1 or SYT-SSX2. In this study, we demonstrate that SYT-SSX2 is a unique oncogene. Rather than confer enhanced proliferation on its target cells, SYT-SSX2 instead causes a profound alteration of their architecture. This aberrant morphology included elongation of the cell body and formation of neurite-like extensions. We also observed that cells transduced with SYT-SSX2 often repulsed one another. Notably, cell repulsion is a known component of ephrin signaling. Further analysis of SYT-SSX2–infected cells revealed significant increases in the expression and activation of Eph/ephrin pathway components. On blockade of EphB2 signaling SYT-SSX2 infectants demonstrated significant reversion of the aberrant cytoskeletal phenotype. In addition, we discovered, in parallel, that SYT-SSX2 induced stabilization of the microtubule network accompanied by accumulation of detyrosinated Glu tubulin and nocodazole resistance. Glu tubulin regulation was independent of ephrin signaling. The clinical relevance of these studies was confirmed by abundant expression of both EphB2 and Glu tubulin in SYT-SSX2–positive synovial sarcoma Tissues. These results indicate that SYT-SSX2 exerts part of its oncogenic effect by altering cytoskeletal architecture in an Eph-dependent manner and cytoskeletal stability through a concurrent and distinct pathway.
Frederic G Barr - One of the best experts on this subject based on the ideXlab platform.
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A fusion transcription factor-driven Cancer progresses to a fusion-independent relapse via constitutive activation of a downstream transcriptional target.
Cancer research, 2021Co-Authors: Salah Boudjadi, Puspa Raj Pandey, Bishwanath Chatterjee, Thanh Hung Nguyen, Wenyue Sun, Frederic G BarrAbstract:Targeted monotherapies usually fail due to development of resistance by a subgroup of cells that evolve into recurrent tumors. Alveolar rhabdomyosarcoma is an aggressive myogenic Soft Tissue Cancer that is associated with a characteristic PAX3-FOXO1 gene fusion encoding a novel fusion transcription factor. In our myoblast model of PAX3-FOXO1-induced rhabdomyosarcoma, de-induction of PAX3-FOXO1 simulates a targeted therapy that antagonizes the fusion oncoprotein. This simulated therapy results initially in regression of the primary tumors, but PAX3-FOXO1-independent recurrent tumors eventually form after a delay. We report here that upregulation of the fibroblast growth factor FGF8, a direct transcriptional target of PAX3-FOXO1, is a mechanism responsible for PAX3-FOXO1-independent tumor recurrence. As a transcriptional target of PAX3-FOXO1, FGF8 promoted oncogenic activity in PAX3-FOXO1-expressing primary tumors that developed in the myoblast system. In the recurrent tumors forming after PAX3-FOXO1 de-induction, FGF8 expression was necessary and sufficient to induce PAX3-FOXO1-independent tumor growth through an autocrine mechanism. FGF8 was also expressed in human PAX3-FOXO1-expressing rhabdomyosarcoma cell lines and contributed to proliferation and transformation. In a human rhabdomyosarcoma cell line with reduced PAX3-FOXO1 expression, FGF8 upregulation rescued oncogenicity and simulated recurrence after PAX3-FOXO1-targeted therapy. We propose that deregulated expression of a PAX3-FOXO1 transcriptional target can generate resistance to therapy directed against this oncogenic transcription factor and postulate that this resistance mechanism may ultimately be countered by therapeutic approaches that antagonize the corresponding downstream pathways.
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examination of gene fusion status in archival samples of alveolar rhabdomyosarcoma entered on the intergroup rhabdomyosarcoma study iii trial a report from the children s oncology group
The Journal of Molecular Diagnostics, 2006Co-Authors: Frederic G Barr, Donna Strzelecki, Lynette M Smith, Stephen J Qualman, David M Parham, James C Lynch, Philip P BreitfeldAbstract:Alveolar rhabdomyosarcoma (ARMS) is a Soft Tissue Cancer in which chromosomal translocations generate PAX3-FKHR and PAX7-FKHR gene fusions. To improve the approach for fusion detection in archival samples, we developed a real-time reverse transcrip-tase-polymerase chain reaction assay for these fusion transcripts. By incorporating consensus primers and gene-specific probes, both presence and subtype of the fusion were determined in one assay. We applied this approach to a convenience sample of 78 formalin-fixed, paraffin-embedded ARMS tumors from the Intergroup Rhabdomyosarcoma Study (IRS)-III clinical trial and obtained satisfactory results in 59 (76%) cases. The distribution of fusion types was 35 (59%) PAX3-FKHR, 11 (19%) PAX7-FKHR, and 13 fusionnegative (22%). In a subsequent clinical analysis, we found that IRS-III ARMS cases analyzed for fusion status had a significantly improved outcome compared to IRS-III ARMS cases that were not available for fusion analysis. The basis of this outcome could not be explained by known prognostic clinical factors, and multivariate analysis confirmed that our convenience sample was not representative of the whole IRS-III cohort. In conclusion, although these robust assays provide new opportunities for correlative studies of archival material, our first application illustrates an important limitation of using a convenience sample for molecular-clinical correlative studies.
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gene fusions involving pax and fox family members in alveolar rhabdomyosarcoma
Oncogene, 2001Co-Authors: Frederic G BarrAbstract:The chromosomal translocations t(2;13)(q35;q14) and t(1;13)(p36;q14) are characteristic of alveolar rhabdomyosarcoma, a pediatric Soft Tissue Cancer related to the striated muscle lineage. These translocations rearrange PAX3 and PAX7, members of the paired box transcription factor family, and juxtapose these genes with FKHR, a member of the fork head transcription factor family. This juxtaposition generates PAX3–FKHR and PAX7–FKHR chimeric genes that are expressed as chimeric transcripts that encode chimeric proteins. The fusion proteins, which contain the PAX3/PAX7 DNA binding domain and the FKHR transcriptional activation domain, activate transcription from PAX-binding sites with higher potency than the corresponding wild-type PAX proteins. This increased function results from the insensitivity of the FKHR activation domain to inhibitory effects of N-terminal PAX3/PAX7 domains. In addition to altered function, the fusion products are expressed in ARMS tumors at higher levels than the corresponding wild-type PAX products due to two distinct mechanisms. The PAX7–FKHR fusion is overexpressed as a result of in vivo amplification while the PAX3–FKHR fusion is overexpressed due to a copy number-independent increase in transcriptional rate. Finally, though FKHR subcellular localization is regulated by an AKT-dependent pathway, the fusion proteins are resistant to these signals and show exclusively nuclear localization. Therefore, these translocations alter biological activity at the levels of protein function, gene expression, and subcellular localization with the cumulative outcome postulated to be aberrant regulation of PAX3/PAX7 target genes. This aberrant gene expression program is then hypothesized to contribute to tumorigenic behavior by impacting on the control of growth, apoptosis, differentiation and motility.
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Chromosomal translocations involving paired box transcription factors in human Cancer
The international journal of biochemistry & cell biology, 1997Co-Authors: Frederic G BarrAbstract:Abstract The PAX genes encode a family of transcription factors that control development within the neural, myogenic, lymphoid, and a variety of other lineages. These proteins are postulated to regulate expression of gene products that function in the control of cellular processes such as proliferation, differentiation, apoptosis, and motility. These same processes are fundamental to the development of Cancer, and thus genetic alterations of these genes may contribute to neoplastic development within these lineages. In support of this premise, several PAX genes have been shown to be targets of consistent chromosomal translocations associated with specific tumor types. The t(2;13) and t(1;13) translocations associated with the myogenic Soft Tissue Cancer alveolar rhabdomyosarcoma fuse portions of the PAX3 or PAX7 gene with a portion of the FKHR gene to generate novel fusion proteins. The t(9;14) translocation associated with the B cell tumor lymphoplasmacytoid lymphoma juxtaposes the PAX5 gene into the vicinity of the IGH locus to deregulate PAX5 expression. This review will examine the molecular basis of these translocations and the role of altered function or expression of paired box transciption factors in the process of tumorigenesis.
Andrea L. Frump - One of the best experts on this subject based on the ideXlab platform.
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Targeting the Wnt Pathway in Synovial Sarcoma Models
Cancer discovery, 2013Co-Authors: Whitney Barham, Christina B. Garcia, Andrea L. Frump, Taylor P. Sherrill, Kenyi Saito-diaz, Michael N. Vansaun, Barbara Fingleton, Linda A. Gleaves, Darren Orton, Mario R. CapecchiAbstract:Synovial sarcoma is an aggressive Soft-Tissue malignancy of children and young adults, with no effective systemic therapies. Its specific oncogene, SYT-SSX (SS18-SSX), drives sarcoma initiation and development. The exact mechanism of SYT-SSX oncogenic function remains unknown. In an SYT-SSX2 transgenic model, we show that a constitutive Wnt/β-catenin signal is aberrantly activated by SYT-SSX2, and inhibition of Wnt signaling through the genetic loss of β-catenin blocks synovial sarcoma tumor formation. In a combination of cell-based and synovial sarcoma tumor xenograft models, we show that inhibition of the Wnt cascade through coreceptor blockade and the use of small-molecule CK1α activators arrests synovial sarcoma tumor growth. We find that upregulation of the Wnt/β-catenin cascade by SYT-SSX2 correlates with its nuclear reprogramming function. These studies reveal the central role of Wnt/β-catenin signaling in SYT-SSX2-induced sarcoma genesis, and open new venues for the development of effective synovial sarcoma curative agents. Synovial sarcoma is an aggressive Soft-Tissue Cancer that afflicts children and young adults, and for which there is no effective treatment. The current studies provide critical insight into our understanding of the pathogenesis of SYT–SSX-dependent synovial sarcoma and pave the way for the development of effective therapeutic agents for the treatment of the disease in humans. ©2013 AACR.
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The synovial sarcoma SYT-SSX2 oncogene remodels the cytoskeleton through activation of the ephrin pathway.
Molecular biology of the cell, 2007Co-Authors: Roy Barco, Christina B. Garcia, Laura B. Hunt, Andrea L. Frump, Andrew E. Benesh, Robert L. Caldwell, Josiane E. EidAbstract:Synovial sarcoma is a Soft Tissue Cancer associated with a recurrent t(X:18) translocation that generates one of two fusion proteins, SYT-SSX1 or SYT-SSX2. In this study, we demonstrate that SYT-SSX2 is a unique oncogene. Rather than confer enhanced proliferation on its target cells, SYT-SSX2 instead causes a profound alteration of their architecture. This aberrant morphology included elongation of the cell body and formation of neurite-like extensions. We also observed that cells transduced with SYT-SSX2 often repulsed one another. Notably, cell repulsion is a known component of ephrin signaling. Further analysis of SYT-SSX2–infected cells revealed significant increases in the expression and activation of Eph/ephrin pathway components. On blockade of EphB2 signaling SYT-SSX2 infectants demonstrated significant reversion of the aberrant cytoskeletal phenotype. In addition, we discovered, in parallel, that SYT-SSX2 induced stabilization of the microtubule network accompanied by accumulation of detyrosinated Glu tubulin and nocodazole resistance. Glu tubulin regulation was independent of ephrin signaling. The clinical relevance of these studies was confirmed by abundant expression of both EphB2 and Glu tubulin in SYT-SSX2–positive synovial sarcoma Tissues. These results indicate that SYT-SSX2 exerts part of its oncogenic effect by altering cytoskeletal architecture in an Eph-dependent manner and cytoskeletal stability through a concurrent and distinct pathway.