Separate cis-trans Pathways Post-transcriptionally Regulate Murine CD154 (CD40 Ligand) Expression

Hamilton, Byron B.; Wang, Xiaowei; Collins, Jane; Bloch, Donald B.; Bergeron, Alan; Henry, Brian; Terry, Benjamin M.; Zan, Moe; Mouland, Andrew J.; Rigby, William F.C.

doi:10.1074/jbc.m802492200

Cited by 22 publications

(23 citation statements)

References 51 publications

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“…The (CA) 24 allele (corresponding to (CA) 26 in our study) appears to confer more stability on its mRNA, and longer alleles confer higher expression levels434548.…”

Section: Discussionmentioning

confidence: 56%

“…Human CD40L is encoded by an unstable mRNA; this instability is conferred by a portion of its 3′UTR including a dual cis-acting element comprising a polypyrimidine-rich region and CA repeats48. It was shown that this CA repeats region is a binding site of nuclear factors and thus could modify the affinity of interaction with CD40LG mRNA and consequently, the translation efficiency484950.…”

Section: Discussionmentioning

confidence: 99%

“…To screen for the maximum number of polymorphisms potentially involved in CD40L protein expression or reported to be associated with immune disorders or inflammation32454864, PCR was performed with eleven primer pairs with corresponding annealing temperatures (Table 3, Supplementary Data S1 for PCR protocols). To promote stable heteroduplex formation, PCR products were denatured for 5 min at 96°C, and then gradually cooled at a rate of 0.5°C per 10 sec over 150 cycles.…”

Section: Methodsmentioning

confidence: 99%

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Are polymorphisms of the immunoregulatory factor CD40LG implicated in acute transfusion reactions?

Aloui

Sut

Prigent

et al. 2014

Sci Rep

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The CD40 ligand (CD40L/CD154), a member of TNF superfamily, is notably expressed on activated CD4+ T-cells and stimulated platelets. CD40L is linked to a variety of pathologies and to acute transfusion reactions (ATR). Mutations in this gene (CD40LG) lead to X-linked hyper-IgM syndrome. Some CD40LG polymorphisms are associated with variable protein expression. The rationale behind this study is that CD40L protein has been observed to be involved in ATR. We wondered whether genetic polymorphisms are implicated. We investigated genetic diversity in the CD40LG using DHPLC and capillary electrophoresis for screening and genotyping (n = 485 French and Tunisian blood donors). We identified significant difference in the CD40LG linkage pattern between the two populations. Variant minor alleles were significantly over-represented in Tunisian donors (P<0.0001 to 0.0270). We found higher heterogeneity in the Tunisian, including three novel low frequency variants. As there was not a particular pattern of CD40LG in single apheresis donors whose platelet components induced an ATR, we discuss how this information may be useful for future disease association studies on CD40LG.

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“…The (CA) 24 allele (corresponding to (CA) 26 in our study) appears to confer more stability on its mRNA, and longer alleles confer higher expression levels434548.…”

Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Are polymorphisms of the immunoregulatory factor CD40LG implicated in acute transfusion reactions?

Aloui

Sut

Prigent

et al. 2014

Sci Rep

View full text Add to dashboard Cite

show abstract

“…We have focused for the last few years on hnRNP L, an abundant nuclear, multifunctional RNA-binding protein with four RNA-recognition motifs (29) that plays both nuclear and cytoplasmic roles in mRNA export of intronless genes (9,18), IRES-mediated translation (10), mRNA stability (11,14,33), and splicing (see below). We have recently characterized in more detail its RNA-binding specificity and function as a global alternative splicing regulator (13,16).…”

mentioning

confidence: 99%

Auto- and Cross-Regulation of the hnRNP L Proteins by Alternative Splicing

Roßbach

Hung

Schreiner

et al. 2009

Molecular and Cellular Biology

121

110

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We recently characterized human hnRNP L as a global regulator of alternative splicing, binding to CArepeat and CA-rich elements. Here we report that hnRNP L autoregulates its own expression on the level of alternative splicing. Intron 6 of the human hnRNP L gene contains a short exon that, if used, introduces a premature termination codon, resulting in nonsense-mediated decay (NMD). This "poison exon" is preceded by a highly conserved CA-rich cluster extending over 800 nucleotides that binds hnRNP L and functions as an unusually extended, intronic enhancer, promoting inclusion of the poison exon. As a result, excess hnRNP L activates NMD of its own mRNA, thereby creating a negative autoregulatory feedback loop and contributing to homeostasis of hnRNP L levels. We present experimental evidence for this mechanism, based on NMD inactivation, hnRNP L binding assays, and hnRNP L-dependent alternative splicing of heterologous constructs. In addition, we demonstrate that hnRNP L cross-regulates inclusion of an analogous poison exon in the hnRNP L-like pre-mRNA, which explains the reciprocal expression of the two closely related hnRNP L proteins.Alternative splicing regulation provides a major mechanism for increasing diversity of gene expression and mediating tissue and developmental control in higher eukaryotes. For many years, studies have focused on mechanisms and factors for a few model genes, but more recently genome-wide approaches have yielded additional insight into the complexity of alternative splicing regulation. Currently, genomewide models attempt to describe networks of relatively few global splicing regulators that act on many target genes in a combinatorial manner. It is often more than a single factor that determines a specific alternative splicing process. These splicing-regulatory networks can be viewed as one of several layers of gene regulation, embedded in other networks such as those of transcription, miRNA-mediated regulation, nonsense-mediated decay (NMD), polyadenylation, translation, or cellular localization (1-3, 6, 21, 25, 34, 36). Most splicing regulators characterized thus far belong to either one of two groups, the family of serine-arginine-rich (SR) proteins and the heterogeneous nuclear ribonucleoproteins (hnRNPs).We have focused for the last few years on hnRNP L, an abundant nuclear, multifunctional RNA-binding protein with four RNA-recognition motifs (29) that plays both nuclear and cytoplasmic roles in mRNA export of intronless genes (9, 18), IRES-mediated translation (10), mRNA stability (11, 14, 33), and splicing (see below). We have recently characterized in more detail its RNA-binding specificity and function as a global alternative splicing regulator (13, 16). Initial evidence for hnRNP L's splicing-regulatory role came from a single human gene, coding for endothelial nitric oxide synthase, which contains in its intron 13 a polymorphic CA repeat region where hnRNP L binds and acts as a splice activator (15). Based on a SELEX-derived consensus for hnRNP L RNA binding, CA-repeat,...

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“…Changes in length of STR (CA) n repeats within cis-regulatory regions can also change gene expression. As previously reported, microsatellites are predictors of nucleotide diversity and divergence[19], and (TG/CA) n repeats are present in the regulation of transcription from disease-related genes such as epidermal growth factor receptor, hydroxysteroid (11-beta) dehydrogenase 2, interferon-gamma, and CD154 [10], [11], [12], [13]. These mounting findings suggest that rs10886471 intronic SNP that causes GRK5 overexpression and the subsequent risk of T2DM may be due to the involvement of intronic STR (CA) n in splicing ( Figure 4 ).…”

Section: Discussionmentioning

confidence: 84%

GRK5 Intronic (CA)n Polymorphisms Associated with Type 2 Diabetes in Chinese Hainan Island

et al. 2014

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A genome-wide association study had showed G-protein–coupled receptor kinase 5 (GRK5) rs10886471 was related to the risk of type 2 diabetes mellitus (T2DM) through upregulated GRK5 mRNA expression. Rs10886471 is located in the intron region of GRK5. However, the mechanism by which intronic SNP affects gene expression remains unclear, whether the effect on gene expression depends on the intronic short tandem repeat (STR) (CA)n splicing regulator or not. Here we investigated the STR (CA)n polymorphism in rs10886471 and further discussed its role in the T2DM risk of Chinese Hainan Island individuals. A total of 1164 subjects were recruited and classified into a normal fasting glucose (NFG) group, an impaired fasting glucose (IFG) group, an impaired glucose tolerance (IGT) group, and a T2DM group. STR (CA)n polymorphisms were detected through polymerase chain reaction and sequencing. Five intronic (CA)n alleles, (CA)15 to (CA)19, were identified in GRK5 rs10886471. Only the (CA)16 allele was significantly associated with increased prediabetes and T2DM risk [odds ratio (OR)>1, P<0.05]. Conversely, multiple alleles without any (CA)16 protected against prediabetes and T2DM (0

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Separate cis-trans Pathways Post-transcriptionally Regulate Murine CD154 (CD40 Ligand) Expression

Cited by 22 publications

References 51 publications

Are polymorphisms of the immunoregulatory factor CD40LG implicated in acute transfusion reactions?

Are polymorphisms of the immunoregulatory factor CD40LG implicated in acute transfusion reactions?

Auto- and Cross-Regulation of the hnRNP L Proteins by Alternative Splicing

GRK5 Intronic (CA)n Polymorphisms Associated with Type 2 Diabetes in Chinese Hainan Island

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