Regulation of Alternative Splicing of CD45 by Antagonistic Effects of SR Protein Splicing Factors

Dam, Gerdy B. ten; Zilch, Christian F.; Wallace, Diana L.; Wieringa, B.; Beverley, Peter C. L.; Poels, L. G.; Screaton, Gavin

doi:10.4049/jimmunol.164.10.5287

Cited by 52 publications

(23 citation statements)

References 67 publications

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“…Employing these two experimental approaches we concluded that the inhibition of CD45 splicing by cAMP-elevating agents was only slightly affected by the actions of these two cytokines and, therefore, other unknown mechanisms may be implicated in preventing CD45RO expression in cAMP-activated cells. It will be of interest to study the role of dbcAMP in regulation of the different proteins of the SR family of splicing factors that has been recently implicated in the alternative splicing of CD45 Ag, leading to either exon inclusion or skipping (3,33).…”

Section: Discussionmentioning

confidence: 99%

Generation of CD4+CD45RA+ Effector T Cells by Stimulation in the Presence of Cyclic Adenosine 5′-Monophosphate- Elevating Agents

Mozo

Gutiérrez

2002

The Journal of Immunology

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After TCR cross-linking, naive CD4+CD45RA+ T cells switch to the expression of the CD45RO isoform and acquire effector functions. In this study we have shown that cAMP-elevating agents added to anti-CD3- and anti-CD28-stimulated cultures of T lymphocytes prevent acquisition of the CD45RO+ phenotype and lead to the generation of a new subpopulation of primed CD4+CD45RA+ effector cells (cAMP-primed CD45RA). These cells displayed a low apoptotic index, as the presence of dibutyryl cAMP (dbcAMP)-rescued cells from CD3/CD28 induced apoptosis. Inhibition of CD45 splicing by dbcAMP was not reverted by addition of exogenous IL-2. cAMP-primed CD45RA cells had a phenotype characteristic of memory/effector T lymphocytes, as they showed an up-regulated expression of CD2, CD44, and CD11a molecules, while the levels of CD62L Ag were down-regulated. These cells also expressed the activation markers CD30, CD71, and HLA class II Ags at an even higher level than CD3/CD28-stimulated cells in the absence of dbcAMP. In agreement with this finding, cAMP-primed CD45RA cells were very efficient in triggering allogenic responses in a MLR. In addition, cAMP-primed CD45RA cells produce considerable amounts of the Th2 cytokines, IL-4, IL-10, and IL-13, whereas the production of IFN-γ and TNF-α was nearly undetectable. The elevated production of IL-13 by neonatal and adult cAMP-primed CD45RA cells was specially noticeable. The cAMP-dependent inhibition of CD45 splicing was not caused by the production of immunosuppressor cytokines. These results suggest that within the pool of CD4+CD45RA+ cells there is a subpopulation of effector lymphocytes generated by activation in the presence of cAMP-elevating agents.

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Section: Discussionmentioning

confidence: 99%

Generation of CD4+CD45RA+ Effector T Cells by Stimulation in the Presence of Cyclic Adenosine 5′-Monophosphate- Elevating Agents

Mozo

Gutiérrez

2002

The Journal of Immunology

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“…This suggests that these SR proteins enhanced the Cµ4-M1 splice reaction relative to cleavagepolyadenylation at the µs poly(A) site. Although some coexpressed SR proteins have been shown to dramatically shift the RNA-splicing patterns of specific substrates in vivo (Caceres et al 1994;Du et al 1997;Bai et al 1999;ten Dam et al 2000), a twofold change in splice ratios has also been reported with other splice substrates (Caceres et al 1994;Screaton et al 1995;Jiang et al 1998;Bai et al 1999). There was no significant change in µ processing with coexpressed SRp40 and SC35 in either cell line (Fig.…”

Section: Splicing Environment Changes Affect µ Rna Processingmentioning

confidence: 99%

“…1B,C). SRp20 has been identified to be a part of a cleavagepolyadenylation enhancer complex (Lou et al 1998), but it also often affects alternatively spliced substrates differently than other SR proteins (e.g., Screaton et al 1995;ten Dam et al 2000). Thus, in the µ pre-mRNA, it is not clear whether SRp20 is enhancing cleavage-polyadenylation or repressing splicing.…”

Section: Splicing Environment Changes Affect µ Rna Processingmentioning

confidence: 99%

B-cell and plasma-cell splicing differences: A potential role in regulated immunoglobulin RNA processing

Bruce¹,

Dingle²,

Peterson³

2003

RNA

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The immunoglobulin µ pre-mRNA is alternatively processed at its 3 end by competing splice and cleavage-polyadenylation reactions to generate mRNAs encoding the membrane-associated or secreted forms of the IgM protein, respectively. The relative use of the competing processing pathways varies during B-lymphocyte development, and it has been established previously that cleavage-polyadenylation activity is higher in plasma cells, which secrete IgM, than in B cells, which produce membraneassociated IgM. To determine whether RNA-splicing activity varies during B-lymphocyte development to contribute to µ RNA-processing regulation, we first demonstrate that µ pre-mRNA processing is sensitive to artificial changes in the splice environment by coexpressing SR proteins with the µ gene. To explore differences between the splice environments of B cells and plasma cells, we analyzed the splicing patterns from two different chimeric non-Ig genes that can be alternatively spliced but have no competing cleavage-polyadenylation reaction. The ratio of intact exon splicing to cryptic splice site use from one chimeric gene differs between several B-cell and several plasma-cell lines. Also, the amount of spliced RNA is higher in B-cell than plasma-cell lines from a set of genes whose splicing is dependent on a functional exonic splice enhancer. Thus, there is clear difference between the B-cell and plasma-cell splicing environments. We propose that both general cleavage-polyadenylation and general splice activities are modulated during B-lymphocyte development to ensure proper regulation of the alternative µ RNA processing pathways.

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“…These proteins are specifically required for cross-exon interactions in both constitutively and alternatively spliced pre-mRNA. Recently, it was shown that relative levels of several SR proteins change upon T cell activation, inducing change in the pattern of CD45 pre-mRNA splicing (11). As other SR proteins, SRp40 recognizes specific 5 to 7 nucleotide-degenerated consensus sequence named exonic splicing enhancers, and at least 29 SRp40-specific exonic splicing enhancers have already been described (12).…”

mentioning

confidence: 99%

Abnormal RNA Processing and Altered Expression of Serin-Rich Proteins in Minimal-Change Nephrotic Syndrome

et al. 2005

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Mechanisms underlying the pathophysiology of minimalchange nephrotic syndrome (MCNS), the most frequent glomerular disease in children, remain elusive, but recent findings argue for a T cell dysfunction. Starting from a differential cDNA library from T cells of a patient under relapse and remission, we identified 16 transcripts specific for MCNS. All of these transcripts that were selectively up-regulated during the relapse phase of the disease were generated by alternative splicing of known genes. This abnormal RNA expression was associated with a down-regulation of serin-rich protein 75 and serin-rich protein 40, two proteins involved in mRNA splicing. Taken together, these data suggest that T cell dysfunction in MCNS is associated with abnormal mRNA splicing. Our understanding of biologic mechanisms that govern physiologic functions as well as pathologic situations has become more complex with recent insights from genome sequencing projects. In particular, it seems that alternative splicing plays a determinant role in the diversity and the complexity of higher organisms (1).Alternative splicing displays a strong tissue specificity or involvement at a defined developmental stage (2). Recent genome-wide data of human alternative pre-mRNA splicing using exon-junction microarrays indicate that at least 74% of human multi-exon genes are alternatively spliced (3). Moreover, that alternative splicing plays a crucial role in the biologic complexity of vertebrates indicates the possibility of its involvement in a large number of human diseases or pathologic processes. Thus, it has been estimated that 15-20% of diseasecausing mutations in human genes involve misregulation of alternative splicing (4).In this report, we reveal the possible involvement of abnormal RNA processing in the pathogenesis of minimal-change nephrotic syndrome (MCNS). This human glomerular disease is characterized by a heavy proteinuria with a relapsing/ remitting course without histologic evidence of classical immune mechanism-mediated injury (5,6). MCNS is a sporadic disease that occurs in the context of immune activation, and its natural course argues strongly against a fixed genetic defect. It is believed that the mechanism of proteinuria involves the secretion by MCNS immune cells of factors that impair the glomerular filtration barrier (7). How the immune response culminates in MCNS by the production of pathogenic factor remains unresolved.Recently, by analyzing a differential T cell cDNA library of a patient under relapse and remission, we identified 16 clones corresponding to unknown transcripts. The nucleotide sequences of these clones all match within intronic sequences of genes with defined or putative functions. Finally, we showed that this abnormal RNA processing is associated with a downregulation of serin-rich protein 75 (SRp75) and SRp40 proteins that play a crucial role in pre-mRNA processing. METHODS Patients.The cohort of patients analyzed in this study has been described previously (8). In all cases, informed consent was obtain...

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Regulation of Alternative Splicing of CD45 by Antagonistic Effects of SR Protein Splicing Factors

Cited by 52 publications

References 67 publications

Generation of CD4+CD45RA+ Effector T Cells by Stimulation in the Presence of Cyclic Adenosine 5′-Monophosphate- Elevating Agents

Generation of CD4+CD45RA+ Effector T Cells by Stimulation in the Presence of Cyclic Adenosine 5′-Monophosphate- Elevating Agents

B-cell and plasma-cell splicing differences: A potential role in regulated immunoglobulin RNA processing

Abnormal RNA Processing and Altered Expression of Serin-Rich Proteins in Minimal-Change Nephrotic Syndrome

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