The Experts below are selected from a list of 28413 Experts worldwide ranked by ideXlab platform
Adrian R Krainer - One of the best experts on this subject based on the ideXlab platform.
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Splicing-Factor alterations in cancers.
RNA (New York N.Y.), 2016Co-Authors: Olga Anczuków, Adrian R KrainerAbstract:Tumor-associated alterations in RNA Splicing result either from mutations in Splicing-regulatory elements or changes in components of the Splicing machinery. This review summarizes our current understanding of the role of Splicing-Factor alterations in human cancers. We describe Splicing-Factor alterations detected in human tumors and the resulting changes in Splicing, highlighting cell-type-specific similarities and differences. We review the mechanisms of Splicing-Factor regulation in normal and cancer cells. Finally, we summarize recent efforts to develop novel cancer therapies, based on targeting either the oncogenic Splicing events or their upstream Splicing regulators.
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emerging functions of srsf1 Splicing Factor and oncoprotein in rna metabolism and cancer
Molecular Cancer Research, 2014Co-Authors: Adrian R KrainerAbstract:Serine/Arginine Splicing Factor 1 (SRSF1) is the archetype member of the SR protein family of Splicing regulators. Since its discovery, over two decades ago, SRSF1 has been repeatedly surprising and intriguing investigators by the plethora of complex biological pathways it regulates. These include several key aspects of mRNA metabolism, such as mRNA Splicing, stability, and translation, as well as other mRNA-independent processes, such as miRNA (miR) processing, protein sumoylation, and the nucleolar-stress response. In this review, the structural features of SRSF1 are discussed as they relate to the intricate mechanism of Splicing and the multiplicity of functions it performs. Similarly, a list of relevant alternatively spliced transcripts and SRSF1 interacting proteins is provided. Finally, emphasis is given to the deleterious consequences of overexpression of the SRSF1 proto-oncogene in human cancers, and the complex mechanisms and pathways underlying SRSF1-mediated transformation. The accumulated knowledge about SRSF1 provides critical insight into the integral role it plays in maintaining cellular homeostasis, and suggests new targets for anti-cancer therapy.
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Splicing Factor srsf6 promotes hyperplasia of sensitized skin
Nature Structural & Molecular Biology, 2014Co-Authors: John E Wilkinson, Mads A Jensen, Adrian R KrainerAbstract:Many biological processes involve gene-expression regulation by alternative Splicing. Here, we identify the Splicing Factor SRSF6 as a regulator of wound healing and tissue homeostasis in skin. We show that SRSF6 is a proto-oncogene frequently overexpressed in human skin cancer. Overexpressing it in transgenic mice induces hyperplasia of sensitized skin and promotes aberrant alternative Splicing. We identify 139 SRSF6-target genes in skin and show that this SR-rich protein binds to alternative exons in the pre-mRNA of the extracellular-matrix protein tenascin C, thus promoting the expression of isoforms characteristic of invasive and metastatic cancer independently of cell type. SRSF6 overexpression additionally results in depletion of LGR6+ stem cells and excessive keratinocyte proliferation and response to injury. Furthermore, the effects of SRSF6 in wound healing assayed in vitro depend on the tenascin-C isoforms. Thus, abnormal SR-protein expression can perturb tissue homeostasis.
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oncogenic Splicing Factor srsf1 is a critical transcriptional target of myc
Cell Reports, 2012Co-Authors: Martin Akerman, Olga Anczuków, Shipra Das, Adrian R KrainerAbstract:The SR protein Splicing Factor SRSF1 is a potent proto-oncogene that is frequently upregulated in cancer. Here, we show that SRSF1 is a direct target of the transcription Factor oncoprotein MYC. These two oncogenes are significantly coexpressed in lung carcinomas, and MYC knockdown downregulates SRSF1 expression in lung-cancer cell lines. MYC directly activates transcription of SRSF1 through two noncanonical E-boxes in its promoter. The resulting increase in SRSF1 protein is sufficient to modulate alternative Splicing of a subset of transcripts. In particular, MYC induction leads to SRSF1-mediated alternative Splicing of the signaling kinase MKNK2 and the transcription Factor TEAD1. SRSF1 knockdown reduces MYC's oncogenic activity, decreasing proliferation and anchorage-independent growth. These results suggest a mechanism for SRSF1 upregulation in tumors with elevated MYC and identify SRSF1 as a critical MYC target that contributes to its oncogenic potential by enabling MYC to regulate the expression of specific protein isoforms through alternative Splicing.
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the Splicing Factor oncoprotein sf2 asf activates mtorc1
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Rotem Karni, Scott W. Lowe, Yoshitaka Hippo, Adrian R KrainerAbstract:The Splicing Factor SF2/ASF is an oncoprotein that is up-regulated in many cancers and can transform immortal rodent fibroblasts when slightly overexpressed. The mTOR signaling pathway is activated in many cancers, and pharmacological blockers of this pathway are in clinical trials as anticancer drugs. We examined the activity of the mTOR pathway in cells transformed by SF2/ASF and found that this Splicing Factor activates the mTORC1 branch of the pathway, as measured by S6K and eIF4EBP1 phosphorylation. This activation is specific to mTORC1 because no activation of Akt, an mTORC2 substrate, was detected. mTORC1 activation by SF2/ASF bypasses upstream PI3K/Akt signaling and is essential for SF2/ASF-mediated transformation, as inhibition of mTOR by rapamycin blocked transformation by SF2/ASF in vitro and in vivo. Moreover, shRNA-mediated knockdown of mTOR, or of the specific mTORC1 and mTORC2 components Raptor and Rictor, abolished the tumorigenic potential of cells overexpressing SF2/ASF. These results suggest that clinical tumors with SF2/ASF up-regulation could be especially sensitive to mTOR inhibitors.
Frank G Harmon - One of the best experts on this subject based on the ideXlab platform.
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spf45 related Splicing Factor for phytochrome signaling promotes photomorphogenesis by regulating pre mrna Splicing in arabidopsis
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Patrice A Salome, Estefania Mancini, Carine M Marshall, Frank G Harmon, Marcelo J Yanovsky, Detlef WeigelAbstract:Abstract Light signals regulate plant growth and development by controlling a plethora of gene expression changes. Posttranscriptional regulation, especially pre-mRNA processing, is a key modulator of gene expression; however, the molecular mechanisms linking pre-mRNA processing and light signaling are not well understood. Here we report a protein related to the human Splicing Factor 45 (SPF45) named Splicing Factor for phytochrome signaling (SFPS), which directly interacts with the photoreceptor phytochrome B (phyB). In response to light, SFPS-RFP (red fluorescent protein) colocalizes with phyB-GFP in photobodies. sfps loss-of-function plants are hyposensitive to red, far-red, and blue light, and flower precociously. SFPS colocalizes with U2 small nuclear ribonucleoprotein-associated Factors including U2AF65B, U2A′, and U2AF35A in nuclear speckles, suggesting SFPS might be involved in the 3′ splice site determination. SFPS regulates pre-mRNA Splicing of a large number of genes, of which many are involved in regulating light signaling, photosynthesis, and the circadian clock under both dark and light conditions. In vivo RNA immunoprecipitation (RIP) assays revealed that SFPS associates with EARLY FLOWERING 3 (ELF3) mRNA, a critical link between light signaling and the circadian clock. Moreover, PHYTOCHROME INTERACTING FactorS (PIFs) transcription Factor genes act downstream of SFPS, as the quadruple pif mutant pifq suppresses defects of sfps mutants. Taken together, these data strongly suggest SFPS modulates light-regulated developmental processes by controlling pre-mRNA Splicing of light signaling and circadian clock genes.
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spf45 related Splicing Factor for phytochrome signaling promotes photomorphogenesis by regulating pre mrna Splicing in arabidopsis
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Ruijiao Xin, Patrice A Salome, Estefania Mancini, Carine M Marshall, Frank G Harmon, Marcelo J Yanovsky, Detlef Weigel, Ling ZhuAbstract:Abstract Light signals regulate plant growth and development by controlling a plethora of gene expression changes. Posttranscriptional regulation, especially pre-mRNA processing, is a key modulator of gene expression; however, the molecular mechanisms linking pre-mRNA processing and light signaling are not well understood. Here we report a protein related to the human Splicing Factor 45 (SPF45) named Splicing Factor for phytochrome signaling (SFPS), which directly interacts with the photoreceptor phytochrome B (phyB). In response to light, SFPS-RFP (red fluorescent protein) colocalizes with phyB-GFP in photobodies. sfps loss-of-function plants are hyposensitive to red, far-red, and blue light, and flower precociously. SFPS colocalizes with U2 small nuclear ribonucleoprotein-associated Factors including U2AF65B, U2A′, and U2AF35A in nuclear speckles, suggesting SFPS might be involved in the 3′ splice site determination. SFPS regulates pre-mRNA Splicing of a large number of genes, of which many are involved in regulating light signaling, photosynthesis, and the circadian clock under both dark and light conditions. In vivo RNA immunoprecipitation (RIP) assays revealed that SFPS associates with EARLY FLOWERING 3 (ELF3) mRNA, a critical link between light signaling and the circadian clock. Moreover, PHYTOCHROME INTERACTING FactorS (PIFs) transcription Factor genes act downstream of SFPS, as the quadruple pif mutant pifq suppresses defects of sfps mutants. Taken together, these data strongly suggest SFPS modulates light-regulated developmental processes by controlling pre-mRNA Splicing of light signaling and circadian clock genes.
Carine M Marshall - One of the best experts on this subject based on the ideXlab platform.
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spf45 related Splicing Factor for phytochrome signaling promotes photomorphogenesis by regulating pre mrna Splicing in arabidopsis
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Patrice A Salome, Estefania Mancini, Carine M Marshall, Frank G Harmon, Marcelo J Yanovsky, Detlef WeigelAbstract:Abstract Light signals regulate plant growth and development by controlling a plethora of gene expression changes. Posttranscriptional regulation, especially pre-mRNA processing, is a key modulator of gene expression; however, the molecular mechanisms linking pre-mRNA processing and light signaling are not well understood. Here we report a protein related to the human Splicing Factor 45 (SPF45) named Splicing Factor for phytochrome signaling (SFPS), which directly interacts with the photoreceptor phytochrome B (phyB). In response to light, SFPS-RFP (red fluorescent protein) colocalizes with phyB-GFP in photobodies. sfps loss-of-function plants are hyposensitive to red, far-red, and blue light, and flower precociously. SFPS colocalizes with U2 small nuclear ribonucleoprotein-associated Factors including U2AF65B, U2A′, and U2AF35A in nuclear speckles, suggesting SFPS might be involved in the 3′ splice site determination. SFPS regulates pre-mRNA Splicing of a large number of genes, of which many are involved in regulating light signaling, photosynthesis, and the circadian clock under both dark and light conditions. In vivo RNA immunoprecipitation (RIP) assays revealed that SFPS associates with EARLY FLOWERING 3 (ELF3) mRNA, a critical link between light signaling and the circadian clock. Moreover, PHYTOCHROME INTERACTING FactorS (PIFs) transcription Factor genes act downstream of SFPS, as the quadruple pif mutant pifq suppresses defects of sfps mutants. Taken together, these data strongly suggest SFPS modulates light-regulated developmental processes by controlling pre-mRNA Splicing of light signaling and circadian clock genes.
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spf45 related Splicing Factor for phytochrome signaling promotes photomorphogenesis by regulating pre mrna Splicing in arabidopsis
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Ruijiao Xin, Patrice A Salome, Estefania Mancini, Carine M Marshall, Frank G Harmon, Marcelo J Yanovsky, Detlef Weigel, Ling ZhuAbstract:Abstract Light signals regulate plant growth and development by controlling a plethora of gene expression changes. Posttranscriptional regulation, especially pre-mRNA processing, is a key modulator of gene expression; however, the molecular mechanisms linking pre-mRNA processing and light signaling are not well understood. Here we report a protein related to the human Splicing Factor 45 (SPF45) named Splicing Factor for phytochrome signaling (SFPS), which directly interacts with the photoreceptor phytochrome B (phyB). In response to light, SFPS-RFP (red fluorescent protein) colocalizes with phyB-GFP in photobodies. sfps loss-of-function plants are hyposensitive to red, far-red, and blue light, and flower precociously. SFPS colocalizes with U2 small nuclear ribonucleoprotein-associated Factors including U2AF65B, U2A′, and U2AF35A in nuclear speckles, suggesting SFPS might be involved in the 3′ splice site determination. SFPS regulates pre-mRNA Splicing of a large number of genes, of which many are involved in regulating light signaling, photosynthesis, and the circadian clock under both dark and light conditions. In vivo RNA immunoprecipitation (RIP) assays revealed that SFPS associates with EARLY FLOWERING 3 (ELF3) mRNA, a critical link between light signaling and the circadian clock. Moreover, PHYTOCHROME INTERACTING FactorS (PIFs) transcription Factor genes act downstream of SFPS, as the quadruple pif mutant pifq suppresses defects of sfps mutants. Taken together, these data strongly suggest SFPS modulates light-regulated developmental processes by controlling pre-mRNA Splicing of light signaling and circadian clock genes.
Detlef Weigel - One of the best experts on this subject based on the ideXlab platform.
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spf45 related Splicing Factor for phytochrome signaling promotes photomorphogenesis by regulating pre mrna Splicing in arabidopsis
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Patrice A Salome, Estefania Mancini, Carine M Marshall, Frank G Harmon, Marcelo J Yanovsky, Detlef WeigelAbstract:Abstract Light signals regulate plant growth and development by controlling a plethora of gene expression changes. Posttranscriptional regulation, especially pre-mRNA processing, is a key modulator of gene expression; however, the molecular mechanisms linking pre-mRNA processing and light signaling are not well understood. Here we report a protein related to the human Splicing Factor 45 (SPF45) named Splicing Factor for phytochrome signaling (SFPS), which directly interacts with the photoreceptor phytochrome B (phyB). In response to light, SFPS-RFP (red fluorescent protein) colocalizes with phyB-GFP in photobodies. sfps loss-of-function plants are hyposensitive to red, far-red, and blue light, and flower precociously. SFPS colocalizes with U2 small nuclear ribonucleoprotein-associated Factors including U2AF65B, U2A′, and U2AF35A in nuclear speckles, suggesting SFPS might be involved in the 3′ splice site determination. SFPS regulates pre-mRNA Splicing of a large number of genes, of which many are involved in regulating light signaling, photosynthesis, and the circadian clock under both dark and light conditions. In vivo RNA immunoprecipitation (RIP) assays revealed that SFPS associates with EARLY FLOWERING 3 (ELF3) mRNA, a critical link between light signaling and the circadian clock. Moreover, PHYTOCHROME INTERACTING FactorS (PIFs) transcription Factor genes act downstream of SFPS, as the quadruple pif mutant pifq suppresses defects of sfps mutants. Taken together, these data strongly suggest SFPS modulates light-regulated developmental processes by controlling pre-mRNA Splicing of light signaling and circadian clock genes.
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spf45 related Splicing Factor for phytochrome signaling promotes photomorphogenesis by regulating pre mrna Splicing in arabidopsis
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Ruijiao Xin, Patrice A Salome, Estefania Mancini, Carine M Marshall, Frank G Harmon, Marcelo J Yanovsky, Detlef Weigel, Ling ZhuAbstract:Abstract Light signals regulate plant growth and development by controlling a plethora of gene expression changes. Posttranscriptional regulation, especially pre-mRNA processing, is a key modulator of gene expression; however, the molecular mechanisms linking pre-mRNA processing and light signaling are not well understood. Here we report a protein related to the human Splicing Factor 45 (SPF45) named Splicing Factor for phytochrome signaling (SFPS), which directly interacts with the photoreceptor phytochrome B (phyB). In response to light, SFPS-RFP (red fluorescent protein) colocalizes with phyB-GFP in photobodies. sfps loss-of-function plants are hyposensitive to red, far-red, and blue light, and flower precociously. SFPS colocalizes with U2 small nuclear ribonucleoprotein-associated Factors including U2AF65B, U2A′, and U2AF35A in nuclear speckles, suggesting SFPS might be involved in the 3′ splice site determination. SFPS regulates pre-mRNA Splicing of a large number of genes, of which many are involved in regulating light signaling, photosynthesis, and the circadian clock under both dark and light conditions. In vivo RNA immunoprecipitation (RIP) assays revealed that SFPS associates with EARLY FLOWERING 3 (ELF3) mRNA, a critical link between light signaling and the circadian clock. Moreover, PHYTOCHROME INTERACTING FactorS (PIFs) transcription Factor genes act downstream of SFPS, as the quadruple pif mutant pifq suppresses defects of sfps mutants. Taken together, these data strongly suggest SFPS modulates light-regulated developmental processes by controlling pre-mRNA Splicing of light signaling and circadian clock genes.
Göran Akusjärvi - One of the best experts on this subject based on the ideXlab platform.
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L4-33K, an Adenovirus-encoded Alternative RNA Splicing Factor
Journal of Biological Chemistry, 2006Co-Authors: Heidi Törmänen, Ellenor Backström, Anette Carlsson, Göran AkusjärviAbstract:Splicing of the adenovirus IIIa mRNA is subjected to a strict temporal regulation during virus infection such that efficient IIIa 3' splice site usage is confined to the late phase of the infectious cycle. Here we show that the adenovirus L4-33K protein functions as a virus-encoded RNA Splicing Factor that preferentially activates Splicing of transcripts with a weak 3' splice site sequence context, a sequence configuration that is shared by many of the late adenovirus 3' splice sites. Furthermore, we show that L4-33K activates IIIa Splicing through the IIIa virus infection-dependent Splicing enhancer element (3VDE). This element was previously shown to be the minimal element, both necessary and sufficient, for activation of IIIa Splicing in the context of an adenovirus-infected cell. L4-33K stimulates an early step in spliceosome assembly and appears to be the only viral protein necessary to convert a nuclear extract prepared from uninfected HeLa cells to an extract with Splicing properties very similar to a nuclear extract prepared from adenovirus late-infected cells. Collectively, our results suggest that L4-33K is the key viral protein required to activate the early to late switch in adenovirus major late L1 alternative Splicing.
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the second rna binding domain of the human Splicing Factor asf sf2 is the critical domain controlling adenovirus e1a alternative 5 splice site selection
Biochemical Journal, 2004Co-Authors: Vita Dauksaite, Göran AkusjärviAbstract:The human Splicing Factor ASF/SF2 (alternative Splicing Factor/Splicing Factor 2) is modular in structure with two RNA-binding domains (RBD1 and RBD2) and a C-terminal domain rich in arginine–serine dipeptide repeats. ASF/SF2 is an essential Splicing Factor that also functions as an important regulator of alternative Splicing. In adenovirus E1A (early region 1A) alternative pre-mRNA Splicing, ASF/SF2 functions as a strong inducer of proximal 5′-splice-site selection, both in vitro and in vivo. In the present study, we tested the functional role of individual domains of ASF/SF2 in alternative Splicing in vitro. We show that ASF/SF2-RBD2 is the critical domain controlling E1A alternative Splicing. In fact, RBD2 alone is sufficient to mimic the activity of the full-length ASF/SF2 protein as an inducer of proximal 5′-splice-site selection in vitro. The RBD2 domain induces a switch to E1A-proximal 5′-splice-site usage by repressing distal 12 S Splicing and simultaneously stimulates proximal 13 S Splicing. In contrast, the ASF/SF2-RBD1 domain has a more general Splicing enhancer phenotype and appears to stimulate preferentially cap-proximal 5′-splice-site selection. Furthermore, the SWQDLKD motif, which is conserved in all SR proteins (serine/arginine-rich proteins) containing two RBDs, and the ribonucleoprotein-1-type RNA recognition motif were both found to be necessary for the alternative splice-site-switching activity of ASF/SF2. The RNP-1 motif was necessary for efficient RNA binding, whereas the SWQDLKD motif most probably contributes by functioning as a surface-mediating critical protein–protein contact during spliceosome assembly.
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the Splicing Factor associated protein p32 regulates rna Splicing by inhibiting asf sf2 rna binding and phosphorylation
The EMBO Journal, 1999Co-Authors: Svend K Petersenmahrt, Camilla Estmer, W. C. Russell, David A. Matthews, Christina Ohrmalm, Göran AkusjärviAbstract:The cellular protein p32 was isolated originally as a protein tightly associated with the essential Splicing Factor ASF/SF2 during its purification from HeLa cells. ASF/SF2 is a member of the SR family of Splicing Factors, which stimulate constitutive Splicing and regulate alternative RNA Splicing in a positive or negative fashion, depending on where on the pre-mRNA they bind. Here we present evidence that p32 interacts with ASF/SF2 and SRp30c, another member of the SR protein family. We further show that p32 inhibits ASF/SF2 function as both a Splicing enhancer and Splicing repressor protein by preventing stable ASF/SF2 interaction with RNA, but p32 does not block SRp30c function. ASF/SF2 is highly phosphorylated in vivo, a modification required for stable RNA binding and protein-protein interaction during spliceosome formation, and this phosphorylation, either through HeLa nuclear extracts or through specific SR protein kinases, is inhibited by p32. Our results suggest that p32 functions as an ASF/SF2 inhibitory Factor, regulating ASF/SF2 RNA binding and phosphorylation. These findings place p32 into a new group of proteins that control RNA Splicing by sequestering an essential RNA Splicing Factor into an inhibitory complex.
