Alternative splicing during chondrogenesis: Modulation of fibronectin exon EIIIA splicing by SR proteins

Kuo, Bruce A.; Uporova, Tatiana M.; Liang, Hongyan; Bennett, Vickie D.; Tuan, Rocky S.; Norton, Pamela A.

doi:10.1002/jcb.10188

Cited by 21 publications

(22 citation statements)

References 52 publications

(60 reference statements)

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“…Thus, higher amounts or activities of certain splice-regulating proteins may lead to a differential pattern of splicing in this individual and therefore to partial phenotype rescue. Recent studies revealed that the modulation of exon splicing by SR proteins depends on the cellular context [Kuo et al, 2002]. As we examined mRNA in lymphoblastoid cells, conclusions concerning different splice patterns in other tissues are not warranted, especially those that may have a higher impact on pathogenesis.…”

Section: Mrna Variations Of Thetrim37 Genementioning

confidence: 95%

A novel splice site mutation in theTRIM37 gene causes mulibrey nanism in a Turkish family with phenotypic heterogeneity

et al. 2003

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Mulibrey nanism (muscle-liver-brain-eye nanism; MUL) is an autosomal recessively transmitted disease characterized by severe growth delays of prenatal onset caused by mutations in the TRIM37 gene. Recent studies on the subcellular localization revealed that the TRIM37 (KIAA0898) protein is located in peroxisomes. Therefore, MUL has been classified as a new peroxisomal disorder. Up to now, four mutations have been reported, all of which lead to frameshifts and truncated proteins. In this study, mutation screening was performed for the coding region of the TRIM37 gene in a Turkish family by means of RT-PCR and direct cDNA sequencing. We have identified a novel mutation resulting in a frameshift cosegregating within the family. Finally, we report on the presence of novel splice variants observed in lymphoblastoid cells and muscle tissue of normal subjects and patients.

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Section: Mrna Variations Of Thetrim37 Genementioning

confidence: 95%

A novel splice site mutation in theTRIM37 gene causes mulibrey nanism in a Turkish family with phenotypic heterogeneity

et al. 2003

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“…SR proteins are well-established regulators of the exon inclusion/exclusion of alternative splicing mechanisms (21)(22)(23)(24). Based on previous findings from our laboratory demonstrating that PP1 activation by de novo ceramide generation can regulate both the phosphorylation status of SR protein and the pre-mRNA processing of caspase-9 (15, 20), we hypothesized that an SR protein isoform is involved in the regulation of the alternative splicing mechanism of caspase-9 pre-mRNA.…”

Section: Srp30a Regulates the Alternative Splicing Of Caspase-9mentioning

confidence: 98%

SRp30a (ASF/SF2) regulates the alternative splicing of caspase-9 pre-mRNA and is required for ceramide-responsiveness

Massiello

Chalfant

2006

Journal of Lipid Research

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Two splice variants are derived from the caspase-9 gene, proapoptotic caspase-9a and antiapoptotic caspase9b, by either the inclusion or exclusion of an exon 3, 4, 5, and 6 cassette. Previous studies from our laboratory have shown that the alternative splicing of caspase-9 and the phosphorylation status of SR proteins, a conserved family of splicing factors, are regulated by chemotherapy and ceramide via the action of protein phosphatase-1. In this study, a link between ceramide, SR proteins, and the alternative splicing of caspase-9 was established. The downregulation of SRp30a in A549 cells by RNA interference technology resulted in an increase in the caspase-9b splice variant, with a concomitant decrease in the caspase-9a splice variant, thereby significantly decreasing the caspase-9a/9b ratio from 1.67 6 0.11 to 0.56 6 0.08 (P , 0.005). The specific downregulation of SRp30a also inhibited the ability of exogenous ceramide treatment to induce the inclusion of the exon 3, 4, 5, and 6 cassette. Therefore, we have identified SRp30a as an RNA trans-acting factor that functions as a major regulator of caspase-9 pre-mRNA processing and is required for ceramide to mediate the alternative splicing of caspase-9.-Massiello, A., and C. E. Chalfant. SRp30a (ASF/SF2) regulates the alternative splicing of caspase-9 pre-mRNA and is required for ceramide-responsiveness. J. Lipid Res. 2006. 47: 892-897. Supplementary key words RNA cis-element . RNA trans-acting factor . A549 cellsCeramide is an important regulator of various stress responses and growth mechanisms, and the formation of ceramide from the hydrolysis of sphingomyelin or from de novo pathways has been observed in response to agonists such as tumor necrosis factor-a, g-interferon, 1a,25-dihydroxyvitamin D 3 , interleukin-1, ultraviolet light, heat, chemotherapeutic agents, fatty acid synthase antigen, and nerve growth factor (1-7). Also, the addition of exogenous ceramide or the enhancement of cellular levels of ceramide induces cell differentiation, cell cycle arrest, apoptosis, or cell senescence in various cell types (8-10). The prominent role of ceramide as a regulator of cellular mechanisms necessitated the identification of target molecules. To this end, a family of ceramide-regulated enzymes has been identified, ceramide-activated protein phosphatases, which include the serine/threonine-specific protein phosphatases PP1 and PP2A (11)(12)(13)(14). With the demonstration of PP1 as a ceramide-activated protein phosphatase, potential PP1 substrates and mechanisms regulated by PP1 became candidate targets for ceramide action.SR proteins, a family of arginine/serine-rich domaincontaining proteins and specific PP1 substrates, are required for constitutive and alternative pre-mRNA processing. Endogenous ceramide was recently found to modulate the phosphorylation status of SR proteins in a PP1-dependent manner (15). Several reports have also demonstrated a role for PP1 in regulating alternative splicing, and two spliceosomal targeting subunits for PP1 ha...

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“…In fact, in many experimental systems, single nucleotide substitutions have been known to affect ESE elements (11,13,14,44). This may be particularly relevant for the EDA exon, as proteins belonging to the SR protein family have a well-known ability to alter EDA inclusion in the mature mRNA (19,40,42). The use of SR scoring matrices to identify potential SR binding sites has been very useful in functionally characterizing several diseasecausing mutations in the BRCA1 and SMN1 genes, as recently reviewed (13).…”

Section: Comparison Of Alternative Splicing Regulation In the Mouse Amentioning

confidence: 99%

RNA Folding Affects the Recruitment of SR Proteins by Mouse and Human Polypurinic Enhancer Elements in the Fibronectin EDA Exon

Buratti

Muro

Giombi

et al. 2004

Molecular and Cellular Biology

110

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In humans, inclusion or exclusion of the fibronectin EDA exon is mainly regulated by a polypurinic enhancer element (exonic splicing enhancer [ESE]) and a nearby silencer element (exonic splicing silencer [ESS]).While human and mouse ESEs behave identically, mutations introduced into the homologous mouse ESS sequence result either in no change in splicing efficiency or in complete exclusion of the exon. Here, we show that this apparently contradictory behavior cannot be simply accounted for by a localized sequence variation between the two species. Rather, the nucleotide differences as a whole determine several changes in the respective RNA secondary structures. By comparing how the two different structures respond to homologous deletions in their putative ESS sequences, we show that changes in splicing behavior can be accounted for by a differential ESE display in the two RNAs. This is confirmed by RNA-protein interaction analysis of levels of SR protein binding to each exon. The immunoprecipitation patterns show the presence of complex multi-SR protein-RNA interactions that are lost with secondary-structure variations after the introduction of ESE and ESS variations. Taken together, our results demonstrate that the sequence context, in addition to the primary sequence identity, can heavily contribute to the making of functional units capable of influencing pre-mRNA splicing.The splicing process is a very flexible and critical step in gene expression. In fact, selected removal or inclusion of individual exons from nascent mRNA molecules allows a single gene to generate multiple proteins with different primary structures; in these cases, the process is known as alternative splicing (1, 38). Constitutive and alternative splicing processes are catalyzed by the spliceosome, a very complex RNA-protein aggregate that has been recently estimated to contain approximately 145 different proteins in addition to the five spliceosomal snRNAs (1,38,41,68). These factors are responsible for accurate positioning of the spliceosome on the 5Ј and 3Ј splice sequences that define the exon. However, correct positioning of the spliceosome is a very complex process owing to the degeneracy of the splice site consensus sequences, the presence of cryptic splice sites in large introns, and the fact that most pre-mRNAs contain multiple introns (26). Therefore, the action of several different proteins is required to achieve accurate positioning of the spliceosome on the splice site. Not surprisingly, alterations in the splicing process have been increasingly reported as being involved in many genetic diseases (5,8,13,23,58). Among the well-known factors that may heavily influence the identification of intron-exon boundaries by the spliceosome are the exon length (3, 65), the presence of splicing enhancer and silencer elements (5, 38), the strength of splicing signals (26), and the promoter architecture (19,33). In addition to these factors, it has been proposed that the natural tendency of RNAs to fold in highly stable secondary and tertia...

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Alternative splicing during chondrogenesis: Modulation of fibronectin exon EIIIA splicing by SR proteins

Cited by 21 publications

References 52 publications

A novel splice site mutation in theTRIM37 gene causes mulibrey nanism in a Turkish family with phenotypic heterogeneity

A novel splice site mutation in theTRIM37 gene causes mulibrey nanism in a Turkish family with phenotypic heterogeneity

SRp30a (ASF/SF2) regulates the alternative splicing of caspase-9 pre-mRNA and is required for ceramide-responsiveness

RNA Folding Affects the Recruitment of SR Proteins by Mouse and Human Polypurinic Enhancer Elements in the Fibronectin EDA Exon

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