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Physiological and Pathological Function of Serine/Arginine-Rich Splicing Factor 4 and Related Diseases.

ABSTRACT: Serine/arginine-rich splicing factors (SRSFs) have one or two RNA recognition motifs in the N terminal and a serine/arginine-enriched domain in the C terminal. SRSFs are essential components of spliceosomes and are involved in alternative splicing, spliceosome assembly, mRNA export, and nonsense-mediated mRNA decay. The maintenance of cellular and tissue homeostasis relies on accurate alternative splicing, and various patterns of abnormal alternative splicing can cause different diseases. SRSF4 is associated with many physiological and pathological processes and has applications in the diagnosis and prognosis of specific diseases. In this review, we discuss knowledge of SRSF4 in physiological and pathological processes and highlight the applications of SRSF4 in the regulation of gene expression and associated diseases.

SUBMITTER: Tan W

PROVIDER: S-EPMC5896335 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Physiological and Pathological Function of Serine/Arginine-Rich Splicing Factor 4 and Related Diseases.

Tan Wanyan W Wang Wei W Ma Qingfeng Q

BioMed research international 20180212

Serine/arginine-rich splicing factors (SRSFs) have one or two RNA recognition motifs in the N terminal and a serine/arginine-enriched domain in the C terminal. SRSFs are essential components of spliceosomes and are involved in alternative splicing, spliceosome assembly, mRNA export, and nonsense-mediated mRNA decay. The maintenance of cellular and tissue homeostasis relies on accurate alternative splicing, and various patterns of abnormal alternative splicing can cause different diseases. SRSF4 ...[more]

PMID: 29789787

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Serine/arginine-rich splicing factor 3 (SRSF3) regulates homologous recombination-mediated DNA repair.

Project description:BackgroundOur previous work found that serine/arginine-rich splicing factor 3 (SRSF3) was overexpressed in human ovarian cancer and the overexpression of SRSF3 was required for ovarian cancer cell growth and survival. The mechanism underlying the role of SRSF3 in ovarian cancer remains to be addressed.MethodsWe conducted microarray analysis to profile the gene expression and splicing in SRSF3-knockdown cells and employed quantitative PCR and western blotting to validate the profiling results. We used chromatin immunoprecipitation to study transcription and the direct repeat green fluorescent protein reporter assay to study homologous recombination-mediated DNA repair (HRR).ResultsWe identified 687 genes with altered expression and 807 genes with altered splicing in SRSF3-knockdown cells. Among expression-altered genes, those involved in HRR, including BRCA1, BRIP1 and RAD51, were enriched and were all downregulated. We demonstrated that the downregulation of BRCA1, BRIP1 and RAD51 expression was caused by decreased transcription and not due to increased nonsense-mediated mRNA decay. Further, we found that SRSF3 knockdown impaired HRR activity in the cell and increased the level of γ-H2AX, a biomarker for double-strand DNA breaks. Finally, we observed that SRSF3 knockdown changed splicing pattern of KMT2C, a H3K4-specific histone methyltransferase, and reduced the levels of mono- and trimethylated H3K4.ConclusionThese results suggest that SRSF3 is a new regulator of HRR process, which possibly regulates the expression of HRR-related genes indirectly through an epigenetic pathway. This new function of SRSF3 not only explains why overexpression of SRSF3 is required for ovarian cancer cell growth and survival but also offers a new insight into the mechanism of the neoplastic transformation.

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A serine-arginine-rich (SR) splicing factor modulates alternative splicing of over a thousand genes in Toxoplasma gondii.

Project description:Single genes are often subject to alternative splicing, which generates alternative mature mRNAs. This phenomenon is widespread in animals, and observed in over 90% of human genes. Recent data suggest it may also be common in Apicomplexa. These parasites have small genomes, and economy of DNA is evolutionarily favoured in this phylum. We investigated the mechanism of alternative splicing in Toxoplasma gondii, and have identified and localized TgSR3, a homologue of ASF/SF2 (alternative-splicing factor/splicing factor 2, a serine-arginine-rich, or SR protein) to a subnuclear compartment. In addition, we conditionally overexpressed this protein, which was deleterious to growth. qRT-PCR was used to confirm perturbation of splicing in a known alternatively-spliced gene. We performed high-throughput RNA-seq to determine the extent of splicing modulated by this protein. Current RNA-seq algorithms are poorly suited to compact parasite genomes, and hence we complemented existing tools by writing a new program, GeneGuillotine, that addresses this deficiency by segregating overlapping reads into distinct genes. In order to identify the extent of alternative splicing, we released another program, JunctionJuror, that detects changes in intron junctions. Using this program, we identified about 2000 genes that were constitutively alternatively spliced in T. gondii. Overexpressing the splice regulator TgSR3 perturbed alternative splicing in over 1000 genes.

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Nuclear Speckle-related Protein 70 Binds to Serine/Arginine-rich Splicing Factors 1 and 2 via an Arginine/Serine-like Region and Counteracts Their Alternative Splicing Activity.

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Deletion of serine/arginine-rich splicing factor 3 in hepatocytes predisposes to hepatocellular carcinoma in mice.

Project description:Alterations in RNA splicing are associated with cancer, but it is not clear whether they result from malignant transformation or have a causative role. We show here that hepatocyte-specific deletion of serine/arginine-rich splicing factor 3 (SRSF3) impairs hepatocyte maturation and metabolism in early adult life, and mice develop spontaneous hepatocellular carcinoma (HCC) with aging. Tumor development is preceded by chronic liver disease with progressive steatosis and fibrosis. SRSF3 protects mice against CCl4 -induced fibrosis and carcinogenesis and suppresses inclusion of the profibrogenic EDA exon in fibronectin 1. Loss of SRSF3 increases expression of insulin-like growth factor 2 and the A-isoform of the insulin receptor, allowing aberrant activation of mitogenic signaling, promotes aberrant splicing and expression of epithelial to mesenchymal transition (EMT) genes, and activates Wnt/?-catenin signaling leading to c-Myc induction. Finally, SRSF3 expression is either decreased or the protein mislocalized in human HCC.Our data suggest a potential role for SRSF3 in preventing hepatic carcinogenesis by regulating splicing to suppress fibrosis, mitogenic splicing, and EMT. Thus, these mice may provide an attractive model to discover the pathogenic mechanisms linking aberrant pre-messenger RNA splicing with liver damage, fibrosis, and HCC.

| S-EPMC4280350 | biostudies-literature

Identification and characterization of a novel serine-arginine-rich splicing regulatory protein.

Project description:We have identified an 86-kDa protein containing a single amino-terminal RNA recognition motif and two carboxy-terminal domains rich in serine-arginine (SR) dipeptides. Despite structural similarity to members of the SR protein family, p86 is clearly unique. It is not found in standard SR protein preparations, does not precipitate in the presence of high magnesium concentrations, is not recognized by antibodies specific for SR proteins, and cannot complement splicing-defective S100 extracts. However, we have found that p86 can inhibit the ability of purified SR proteins to activate splicing in S100 extracts and can even inhibit the in vitro and in vivo activation of specific splice sites by a subset of SR proteins, including ASF/SF2, SC35, and SRp55. In contrast, p86 activates splicing in the presence of SRp20. Thus, it appears that pairwise combination of p86 with specific SR proteins leads to altered splicing efficiency and differential splice site selection. In all cases, such regulation requires the presence of the two RS domains and a unique intervening EK-rich region, which appear to mediate direct protein-protein contact between these family members. Full-length p86, but not a mutant lacking the RS-EK-RS domains, was found to preferentially interact with itself, SRp20, ASF/SF2, SRp55, and, to a slightly lesser extent, SC35. Because of the primary sequence and unique properties of p86, we have named this protein SRrp86 for SR-related protein of 86 kDa.

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Protein kinase a-dependent phosphorylation of serine 119 in the proto-oncogenic serine/arginine-rich splicing factor 1 modulates its activity as a splicing enhancer protein.

Project description:Serine/arginine-rich splicing factor 1 (SRSF1), previously designated SF2/ASF, belongs to a family of SR proteins that regulate constitutive and alternative splicing. SRSF1 expression is increased in tumors from several tissues and elicits changes in key target genes involved in tumor genesis. Several protein kinases phosphorylate SRSF1, which regulates its localization and function. It is previously reported that protein kinase A (PKA) phosphorylates SRSF1, but the importance of this modification is not well characterized. Here, we show that PKA phosphorylates SRSF1 on serine 119 in vitro. Phosphorylation of SRSF1 on this site enhanced the RNA binding capacity of SRSF1 in vivo and reduced the protein's capacity to activate splicing of the Minx transcript in vitro. We also confirm an interaction between SRSF1 and PKA C?1 and demonstrate that this interaction is not dependent on serine 119 phosphorylation but requires active PKA C?1. We conclude that PKA phosphorylation of SRSF1 at serine 119 regulates SFRS1-dependent RNA binding and processing but not its interaction with PKA.

| S-EPMC3278900 | biostudies-literature

Serine/arginine-rich splicing factors belong to a class of intrinsically disordered proteins.

Project description:Serine/arginine-rich (SR) splicing factors play an important role in constitutive and alternative splicing as well as during several steps of RNA metabolism. Despite the wealth of functional information about SR proteins accumulated to-date, structural knowledge about the members of this family is very limited. To gain a better insight into structure-function relationships of SR proteins, we performed extensive sequence analysis of SR protein family members and combined it with ordered/disordered structure predictions. We found that SR proteins have properties characteristic of intrinsically disordered (ID) proteins. The amino acid composition and sequence complexity of SR proteins were very similar to those of the disordered protein regions. More detailed analysis showed that the SR proteins, and their RS domains in particular, are enriched in the disorder-promoting residues and are depleted in the order-promoting residues as compared to the entire human proteome. Moreover, disorder predictions indicated that RS domains of SR proteins were completely unstructured. Two different classification methods, the charge-hydropathy measure and the cumulative distribution function (CDF) of the disorder scores, were in agreement with each other, and they both strongly predicted members of the SR protein family to be disordered. This study emphasizes the importance of the disordered structure for several functions of SR proteins, such as for spliceosome assembly and for interaction with multiple partners. In addition, it demonstrates the usefulness of order/disorder predictions for inferring protein structure from sequence.

| S-EPMC1326245 | biostudies-literature

Splicosomal and serine and arginine-rich splicing factors as targets for TGF-β.

Project description:BackgroundTransforming growth factor-β1 (TGF-β1) is a potent regulator of cell growth and differentiation. TGF-β1 has been shown to be a key player in tissue remodeling processes in a number of disease states by inducing expression of extracellular matrix proteins. In this study a quantitative proteomic analysis was undertaken to investigate if TGF-β1 contributes to tissue remodeling by mediating mRNA splicing and production of alternative isoforms of proteins.Methodology/principal findingsThe expression of proteins involved in mRNA splicing from TGF-β1-stimulated lung fibroblasts was compared to non-stimulated cells by employing isotope coded affinity tag (ICATTM) reagent labeling and tandem mass spectrometry. A total of 1733 proteins were identified and quantified with a relative standard deviation of 11% +/- 8 from enriched nuclear fractions. Seventy-six of these proteins were associated with mRNA splicing, including 22 proteins involved in splice site selection. In addition, TGF-β1 was observed to alter the relative expression of splicing proteins that may be important for alternative splicing of fibronectin. Specifically, TGF-β1 significantly induced expression of SRp20, and reduced the expression of SRp30C, which has been suggested to be a prerequisite for generation of alternatively spliced fibronectin. The induction of SRp20 was further confirmed by western blot and immunofluorescence.ConclusionsThe results show that TGF-β1 induces the expression of proteins involved in mRNA splicing and RNA processing in human lung fibroblasts. This may have an impact on the production of alternative isoforms of matrix proteins and can therefore be an important factor in tissue remodeling and disease progression.

| S-EPMC3472233 | biostudies-literature

Identification of a plant serine-arginine-rich protein similar to the mammalian splicing factor SF2/ASF.

Project description:We show that the higher plant Arabidopsis thaliana has a serine-arginine-rich (SR) protein family whose members contain a phosphoepitope shared by the animal SR family of splicing factors. In addition, we report the cloning and characterization of a cDNA encoding a higher-plant SR protein from Arabidopsis, SR1, which has striking sequence and structural homology to the human splicing factor SF2/ASF. Similar to SF2/ASF, the plant SR1 protein promotes splice site switching in mammalian nuclear extracts. A novel feature of the Arabidopsis SR protein is a C-terminal domain containing a high concentration of proline, serine, and lysine residues (PSK domain), a composition reminiscent of histones. This domain includes a putative phosphorylation site for the mitotic kinase cyclin/p34cdc2.

| S-EPMC41207 | biostudies-other

Phosphorylation of serine/arginine-rich splicing factor 1 at tyrosine 19 promotes cell proliferation in pediatric acute lymphoblastic leukemia.

Project description:Serine/arginine-rich splicing factor 1 (SRSF1) has been linked to various human cancers including pediatric acute lymphoblastic leukemia (ALL). Our previous study has shown that SRSF1 potentially contributes to leukemogenesis; however, its underlying mechanism remains unclear. In this study, leukemic cells were isolated from pediatric ALL bone marrow samples, followed by immunoprecipitation assays and mass spectrometry analysis specific to SRSF1. Subcellular localization of the SRSF1 protein and its mutants were analyzed by immunofluorescence staining. Cell growth, colony formation, cell apoptosis, and the cell cycle were investigated using stable leukemic cell lines generated with lentivirus-mediated overexpressed WT or mutant plasmids. Cytotoxicity of the Tie2 kinase inhibitor was also evaluated. Our results showed the phosphorylation of SRSF1 at tyrosine 19 (Tyr-19) was identified in newly diagnosed ALL samples, but not in complete remission or normal control samples. Compared to the SRSF1 WT cells, the missense mutants of the Tyr-19 phosphorylation affected the subcellular localization of SRSF1. In addition, the Tyr-19 phosphorylation of SRSF1 also led to increased cell proliferation and enhanced colony-forming properties by promoting the cell cycle. Remarkably, we further identified the kinase Tie2 as a potential therapeutic target in leukemia cells. In conclusion, we identify for the first time that the phosphorylation state of SRSF1 is linked to different phases in pediatric ALL. The Tyr-19 phosphorylation of SRSF1 disrupts its subcellular localization and promotes proliferation in leukemia cells by driving cell-cycle progression. Inhibitors targeting Tie2 kinase that could catalyze Tyr-19 phosphorylation of SRSF1 offer a promising therapeutic target for treatment of pediatric ALL.

| S-EPMC6272096 | biostudies-literature

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