The Polyadenylation Factor CstF-64 Regulates Alternative Processing of IgM Heavy Chain Pre-mRNA during B Cell Differentiation

Takagaki, Yoshio; Seipelt, Rebecca L.; Peterson, Martha L.; Manley, James L.

doi:10.1016/s0092-8674(00)82000-0

Cited by 380 publications

(385 citation statements)

References 46 publications

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“…These factors seem to change the use of the internal polyadenylation site, without affecting the efficiency of the external site. For instance, high levels of the polyadenylation factor CstF-64 facilitate the use of the internal site [13], U1A binding to motifs around the l polyadenylation site hinders its use [20], and efficient polyadenylation and cleavage of the secreted form of the a HC is dependent on a cis-acting factor [18]. The mechanism described here for the e HC sets a high transcriptional threshold for mIgE expression in the early phase of the immune response.…”

Section: Discussionmentioning

confidence: 93%

“…The choice depends normally on the developmental stage of the B cell [11][12][13][14][15]. In resting B cells the ratio is approximately 1 : 1 for the mu (l) HC, but this ratio shifts in favor of the secreted form in plasma cells, resulting in a ratio of approximately 1 : 100 for the membrane (ml) versus the secreted form (sl), respectively.…”

Section: Introductionmentioning

confidence: 99%

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Inefficient processing of mRNA for the membraneform of IgE is a genetic mechanism to limit recruitment of IgE‐secreting cells

et al. 2006

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Immunoglobulin E (IgE) is the key effector element in allergic diseases ranging from innocuous hay fever to life-threatening anaphylactic shock. Compared to other Ig classes, IgE serum levels are very low. In its membrane-bound form (mIgE), IgE behaves as a classical antigen receptor on B lymphocytes. Expression of mIgE is essential for subsequent recruitment of IgE-secreting cells. We show that in activated, mIgE-bearing B cells, mRNA for the membrane forms of both murine and human epsilon (e) heavy chains (HC) are poorly expressed compared to mRNA for the secreted forms. In contrast, in mIgG-bearing B cells, mRNA for the membrane forms of murine gamma-1 (c1) and the corresponding human c4 HC are expressed at a much higher level than mRNA for the respective secreted forms. We show that these findings correlate with the presence of deviant polyadenylation signal hexamers in the 3 0 untranslated region (UTR) of both murine and human e genes, causing inefficient processing of primary transcripts and thus poor expression of the proteins and poor recruitment of IgEproducing cells in the immune response. Thus, we have identified a genetic steering mechanism in the regulation of IgE synthesis that represents a further means to restrain potentially dangerous, high serum IgE levels.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Inefficient processing of mRNA for the membraneform of IgE is a genetic mechanism to limit recruitment of IgE‐secreting cells

et al. 2006

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“…Alternatively, in pre-B cells, splicing wins so that the intronic PAS is suppressed, and instead a downstream PAS is used with additional terminal exons included in the heavy chain mRNA. This process is regulated by levels of CStF-64, which are more limited in pre-B cells than in mature B cells (Takagaki et al 1996;Takagaki and Manley 1998). Also, Pol II elongation factors may act to modulate this PAS switch (Martincic et al 2009).…”

Section: Alternative Pas (Apa) Define Different Mrna 39 Utrsmentioning

confidence: 99%

Ending the message: poly(A) signals then and now

Proudfoot¹

2011

Genes Dev.

520

486

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Polyadenylation [poly(A)] signals (PAS) are a defining feature of eukaryotic protein-coding genes. The central sequence motif AAUAAA was identified in the mid1970s and subsequently shown to require flanking, auxiliary elements for both 39-end cleavage and polyadenylation of premessenger RNA (pre-mRNA) as well as to promote downstream transcriptional termination. More recent genomic analysis has established the generality of the PAS for eukaryotic mRNA. Evidence for the mechanism of mRNA 39-end formation is outlined, as is the way this RNA processing reaction communicates with RNA polymerase II to terminate transcription. The widespread phenomenon of alternative poly(A) site usage and how this interrelates with pre-mRNA splicing is then reviewed. This shows that gene expression can be drastically affected by how the message is ended. A central theme of this review is that while genomic analysis provides generality for the importance of PAS selection, detailed mechanistic understanding still requires the direct analysis of specific genes by genetic and biochemical approaches.

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“…[28][29][30][31][32] Several polyadenylation factors have been implicated in APA including CF1m 33,34 and CstF. 35,36 For example, knockdown of CF1m25 (CF1m25 KD) or CstF64 (CstF64 KD) has been shown to result in the activation of alternative poly(A) sites. 34,36 Thus, APA events are mediated through factors that are also engaged in interactions with spliceosomal components.…”

Section: Introductionmentioning

confidence: 99%

Coupling between alternative polyadenylation and alternative splicing is limited to terminal introns

et al. 2016

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Alternative polyadenylation has been implicated as an important regulator of gene expression. In some cases, alternative polyadenylation is known to couple with alternative splicing to influence last intron removal. However, it is unknown whether alternative polyadenylation events influence alternative splicing decisions at upstream exons. Knockdown of the polyadenylation factors CFIm25 or CstF64 in HeLa cells was used as an approach in identifying alternative polyadenylation and alternative splicing events on a genome-wide scale. Although hundreds of alternative splicing events were found to be differentially spliced in the knockdown of CstF64, genes associated with alternative polyadenylation did not exhibit an increased incidence of alternative splicing. These results demonstrate that the coupling between alternative polyadenylation and alternative splicing is usually limited to defining the last exon. The striking influence of CstF64 knockdown on alternative splicing can be explained through its effects on UTR selection of known splicing regulators such as hnRNP A2/B1, thereby indirectly influencing splice site selection. We conclude that changes in the expression of the polyadenylation factor CstF64 influences alternative splicing through indirect effects.

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The Polyadenylation Factor CstF-64 Regulates Alternative Processing of IgM Heavy Chain Pre-mRNA during B Cell Differentiation

Cited by 380 publications

References 46 publications

Inefficient processing of mRNA for the membraneform of IgE is a genetic mechanism to limit recruitment of IgE‐secreting cells

Inefficient processing of mRNA for the membraneform of IgE is a genetic mechanism to limit recruitment of IgE‐secreting cells

Ending the message: poly(A) signals then and now

Coupling between alternative polyadenylation and alternative splicing is limited to terminal introns

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