Regulation of Alternative Splicing of Human Tau Exon 10 by Phosphorylation of Splicing Factors

Hartmann, Annette M.; Rujescu, Dan; Giannakouŕos, Thomas; Nikolakaki, Eleni; Goedert, Michel; Mandelkow, Eva‐Maria; Gao, Qing; Andreadis, Athena; Stamm, Stefan

doi:10.1006/mcne.2001.1000

Cited by 103 publications

(84 citation statements)

References 93 publications

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“…Pathway analysis showed that these genes were functionally linked to RNA splicing and noncoding RNA processing, suggesting that RNA processing and splicing are affected in CA1 neurons during aging ( Figure 2B). To validate this finding, we measured protein levels of the dual specificity kinase CLK1, which is a critical regulator of the spliceosome and has been linked to alternative splicing (24)(25)(26). Consistent with our RNA-seq data, the levels of CLK1 were decreased in aged animals (Supplemental Figure 3).…”

Section: Introductionsupporting

confidence: 69%

HDAC inhibitor–dependent transcriptome and memory reinstatement in cognitive decline models

Benito

Urbanke

Ramachandran

et al. 2015

Journal of Clinical Investigation

169

137

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Section: Introductionsupporting

confidence: 69%

HDAC inhibitor–dependent transcriptome and memory reinstatement in cognitive decline models

Benito

Urbanke

Ramachandran

et al. 2015

Journal of Clinical Investigation

169

137

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“…Three other Clk family members have interesting roles in specific contexts, including insulin response, splicing of exons involved in neuronal tauopathies, and the replication cycle of HIV (Duncan et al 1998;Hartmann et al 2001;Jiang et al 2009;Rodgers et al 2010;Wong et al 2011). These studies suggest that Clk kinases, through regulation of splicing, are positioned to channel multiple cellular signaling pathways in different cell types and disease states, including global stress responses.…”

Section: à16mentioning

confidence: 97%

Detained introns are a novel, widespread class of post-transcriptionally spliced introns

2015

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Deep sequencing of embryonic stem cell RNA revealed many specific internal introns that are significantly more abundant than the other introns within polyadenylated transcripts; we classified these as ''detained'' introns (DIs). We identified thousands of DIs, many of which are evolutionarily conserved, in human and mouse cell lines as well as the adult mouse liver. DIs can have half-lives of over an hour yet remain in the nucleus and are not subject to nonsense-mediated decay (NMD). Drug inhibition of Clk, a stress-responsive kinase, triggered rapid splicing changes for a specific subset of DIs; half showed increased splicing, and half showed increased intron detention, altering transcript pools of >300 genes. Srsf4, which undergoes a dramatic phosphorylation shift in response to Clk kinase inhibition, regulates the splicing of some DIs, particularly in genes encoding RNA processing and splicing factors. The splicing of some DIs-including those in Mdm4, a negative regulator of p53-was also altered following DNA damage. After 4 h of Clk inhibition, the expression of >400 genes changed significantly, and almost one-third of these are p53 transcriptional targets. These data suggest a widespread mechanism by which the rate of splicing of DIs contributes to the level of gene expression.

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“…In this respect we have previously shown that SRPK1 was able to regulate the alternative splicing of human tau exon 10 in transfected cells (45). To determine whether SRPK1a had an effect similar to that of SRPK1, we tested both isoforms in co-transfection experiments with the tau minigene SV9 -10L-11 consisting of exon 10 and its flanking exon and intron regions ( Fig.…”

Section: Fig 3 Expression Of Srpk1a In Mammalian Cellsmentioning

confidence: 99%

Cloning and Characterization of an Alternatively Spliced Form of SR Protein Kinase 1 That Interacts Specifically with Scaffold Attachment Factor-B

Nikolakaki

Kohen

Hartmann

et al. 2001

Journal of Biological Chemistry

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Serine/arginine protein kinases have been conserved throughout evolution and are thought to play important roles in the regulation of mRNA processing, nuclear import, germline development, polyamine transport, and ion homeostasis. Human SRPK1, which was first identified as a kinase specific for the SR family of splicing factors, is located on chromosome 6p21.2-p21.3. We report here the cloning and characterization of SRPK1a, which is encoded by an alternatively processed transcript derived from the SRPK1 gene. SRPK1a contains an insertion of 171 amino acids at its NH 2 -terminal domain and is similar to SRPK1 in substrate specificity and subcellular localization. . Mammalian SRPK1 and SRPK2, which are highly related in sequence, kinase activity, and substrate specificity, were initially purified and cloned on the basis of their ability to phosphorylate members of the SR family of splicing factors in vitro and mediate splicing factor redistribution during the cell cycle (1-4). SR proteins themselves constitute a highly conserved protein family that is intimately involved in the regulation of pre-mRNA splicing and other steps of RNA metabolism (for reviews, see Refs. 5-7). Biochemical studies demonstrated that SR proteins are required at multiple steps in the assembly of the spliceosome, the dynamic RNA-protein complex that catalyzes intron removal (8 -10). Because RS domains are known to participate in protein-protein and protein-RNA interactions during spliceosome assembly, phosphorylation of these domains can modulate interactions involving SR proteins and is, therefore, essential for their function in constitutive splicing (3,11,12). Furthermore, phosphorylation of SR proteins leads to their release from nuclear speckles, in which they are concentrated to active sites of transcription in the nucleoplasm (1, 3, 13-15). Because changes in the intranuclear SR protein concentration play a critical role in determining which of the competing splice sites are selected, phosphorylation can also indirectly control alternative splice site selection (16 -20). Finally, it has been proposed that the formation of complexes between SF2/ASF and SRPKs may modulate the subcellular distribution of SF2/ASF (21).Yet, the lack both of authentic SR proteins in the yeast genome and of alternative mRNA splicing in yeast suggests that these kinases play roles in the regulation of cellular processes in addition to that of mRNA splicing. Indeed, genetic analyses have implicated Dsk1, which is the fission yeast homologue of SRPK1 in the regulation of chromosome segregation at the metaphase/anaphase transition (22). Furthermore, one of the endogenous substrates of Sky1p, in S. cerevisiae, is the RNA binding protein Npl3p, which has been implicated in mRNA transport (23). Sky1p was found to regulate nuclear import of Npl3p by promoting the interaction between Npl3p

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Regulation of Alternative Splicing of Human Tau Exon 10 by Phosphorylation of Splicing Factors

Cited by 103 publications

References 93 publications

HDAC inhibitor–dependent transcriptome and memory reinstatement in cognitive decline models

HDAC inhibitor–dependent transcriptome and memory reinstatement in cognitive decline models

Detained introns are a novel, widespread class of post-transcriptionally spliced introns

Cloning and Characterization of an Alternatively Spliced Form of SR Protein Kinase 1 That Interacts Specifically with Scaffold Attachment Factor-B

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