CDC2L5, a Cdk‐like kinase with RS domain, interacts with the ASF/SF2‐associated protein p32 and affects splicing in vivo

Even, Yasmine; Durieux, Sandrine; Escande, Marie‐Line; Lozano, Jean Claude; Peaucellier, Gérard; Weil, Dominique; Genevière, Anne-Marie

doi:10.1002/jcb.20986

Cited by 55 publications

(82 citation statements)

References 43 publications

(56 reference statements)

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“…8). Expression of active CDK11 p110WT caused a slight change in E1A splice site usage resulting in the production of more 9S transcript, although this effect was less than the 2-3-fold increases in 9S seen following CDK12 and CDK13 expression (2)(3)(4). On the other hand, expression of inactive CDK11 p110DN decreased production of the 9S splice form and considerably increased 13 and 11S splice form levels, an effect similarly observed when endogenous CDK12 expression was decreased using RNA interference (2).…”

Section: Discussionmentioning

confidence: 79%

“…Finally, we demonstrate that expression of cyclins L␣ and -␤ and CDK11 p110 strongly and differentially affects alternative splicing in vivo. Together, these data establish that CDK11 p110 interacts physically and functionally with cyclin L␣ and -␤ isoforms and SR proteins to regulate splicing.It has become apparent over the past decade that several cyclin-dependent kinases (CDKs) 4 and their cyclin regulatory partners participate in regulating mRNA production (1). Thus far, CDK7, CDK8, and CDK9 functions are ascribed to transcriptional initiation and elongation, and CDK12 (CrkRS) and CDK13 (CDC2L5) functions are related to pre-mRNA splicing (2-4).…”

mentioning

confidence: 99%

“…It has become apparent over the past decade that several cyclin-dependent kinases (CDKs) 4 and their cyclin regulatory partners participate in regulating mRNA production (1). Thus far, CDK7, CDK8, and CDK9 functions are ascribed to transcriptional initiation and elongation, and CDK12 (CrkRS) and CDK13 (CDC2L5) functions are related to pre-mRNA splicing (2)(3)(4).…”

mentioning

confidence: 99%

“…Thus far, CDK7, CDK8, and CDK9 functions are ascribed to transcriptional initiation and elongation, and CDK12 (CrkRS) and CDK13 (CDC2L5) functions are related to pre-mRNA splicing (2)(3)(4). Interestingly, CDK11 p110 plays roles in both transcription and splicing, suggesting that this CDK may link the two processes (5,6).…”

mentioning

confidence: 99%

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Characterization of Cyclin L1 and L2 Interactions with CDK11 and Splicing Factors

Loyer

Trembley

Grenet

et al. 2008

Journal of Biological Chemistry

122

137

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Although it has been reported that cyclin L1␣ and L2␣ proteins interact with CDK11 p110 , the nature of the cyclin L transcripts, the formation of complexes between the five cyclin L and the three CDK11 protein isoforms, and the influence of these complexes on splicing have not been thoroughly investigated. Here we report that cyclin L1 and L2 genes generate 14 mRNA variants encoding six cyclin L proteins, one of which has not been described previously. Using cyclin L gene-specific antibodies, we demonstrate expression of multiple endogenous cyclin L proteins in human cell lines and mouse tissues. Moreover, we characterize interactions between CDK11 p110 , mitosis-specific CDK11 p58 , and apoptosis-specific CDK11 p46 with both cyclin L␣ and -␤ proteins and the co-elution of these proteins following size exclusion chromatography. We further establish that CDK11 p110 and associated cyclin L␣/␤ proteins localize to splicing factor compartments and nucleoplasm and interact with serine/arginine-rich proteins. Importantly, we also determine the effect of CDK11-cyclin L complexes on pre-mRNA splicing. Preincubation of nuclear extracts with purified cyclin L␣ and -␤ isoforms depletes the extract of in vitro splicing activity. Ectopic expression of cyclin L1␣, L1␤, L2␣, or L2␤ or active CDK11 p110 individually enhances intracellular intron splicing activity, whereas expression of CDK11 p58/p46 or kinase-dead CDK11 p110 represses splicing activity. Finally, we demonstrate that expression of cyclins L␣ and -␤ and CDK11 p110 strongly and differentially affects alternative splicing in vivo. Together, these data establish that CDK11 p110 interacts physically and functionally with cyclin L␣ and -␤ isoforms and SR proteins to regulate splicing.It has become apparent over the past decade that several cyclin-dependent kinases (CDKs) 4 and their cyclin regulatory partners participate in regulating mRNA production (1). Thus far, CDK7, CDK8, and CDK9 functions are ascribed to transcriptional initiation and elongation, and CDK12 (CrkRS) and CDK13 (CDC2L5) functions are related to pre-mRNA splicing (2-4). Interestingly, CDK11 p110 plays roles in both transcription and splicing, suggesting that this CDK may link the two processes (5, 6). In addition, the CDK11 p110 partner proteins cyclins L1 and L2 also influence splicing (7,8). Two distinct genes, Cdc2L1 and Cdc2L2 (acronym for Cell division control 2 Like), encode the human p110 and p58 PITSLRE protein kinases (9 -12). These kinases were renamed CDK11 p110 and CDK11 p58 when cyclins L1 and L2 were identified as regulatory subunits of CDK11 p110 (13). Expression of the CDK11 p110 isoforms is ubiquitous and constant throughout the cell cycle (11). In contrast, CDK11 p58 is expressed and functions specifically in G 2 /M via an internal ribosome entry site (IRES) located within the CDK11 p110 mRNA (14 -17). During apoptosis, a third isoform, CDK11 p46 , is generated by caspase-dependent cleavage of CDK11 p110 and CDK11 p58 , leaving the catalytic domain intact (18,19).A role for CDK11 p...

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Section: Discussionmentioning

confidence: 79%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Characterization of Cyclin L1 and L2 Interactions with CDK11 and Splicing Factors

Loyer

Trembley

Grenet

et al. 2008

Journal of Biological Chemistry

122

137

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“…Neverthless, emerging evidence has shown that CDK12 contains the arginine/serine domain and is involved in RNA processing (32,33). In addition, CDK12 has been implicated in mRNA splicing (15,34,35). However, from our data, we cannot exclude the possibility that the arginine/serine domain of CDK12 also contributes to heterochromatin remodeling.…”

Section: Discussionmentioning

confidence: 99%

Heterochromatin remodeling by CDK12 contributes to learning in Drosophila

Pan

Xie

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Dynamic regulation of chromatin structure is required to modulate the transcription of genes in eukaryotes. However, the factors that contribute to the plasticity of heterochromatin structure are elusive. Here, we report that cyclin-dependent kinase 12 (CDK12), a transcription elongation-associated RNA polymerase II (RNAPII) kinase, antagonizes heterochromatin enrichment in Drosophila chromosomes. Notably, loss of CDK12 induces the ectopic accumulation of heterochromatin protein 1 (HP1) on euchromatic arms, with a prominent enrichment on the X chromosome. Furthermore, ChIP and sequencing analysis reveals that the heterochromatin enrichment on the X chromosome mainly occurs within long genes involved in neuronal functions. Consequently, heterochromatin enrichment reduces the transcription of neuronal genes in the adult brain and results in a defect in Drosophila courtship learning. Taken together, these results define a previously unidentified role of CDK12 in controlling the epigenetic transition between euchromatin and heterochromatin and suggest a chromatin regulatory mechanism in neuronal behaviors.A ppropriate regulation of gene transcription is essential throughout the life of an organism. In eukaryotes, DNA and histone octamers are assembled into nucleosomes and further compacted into higher-order structures (1). Dynamic changes in the chromatin architecture affect gene transcription in many aspects of developmental and physiological processes, such as neural plasticity, memory formation, and cognition (2, 3). Eukaryotic genomes are composed of two basic forms, euchromatin and heterochromatin, which are originally characterized by their cytological chromatin packaging levels. Euchromatic regions are generally associated with a relatively open chromatin configuration and mainly contain transcriptionally active genes, whereas heterochromatin is highly compacted and less accessible to the transcriptional machinery (4). Drosophila heterochromatin is mainly localized at the pericentric and subtelomeric regions and enriched for methylation of histone H3 on Lys9 (H3K9me), which provides a docking site for heterochromatin protein 1 (HP1) (5, 6), a highly conserved protein involved in heterochromatin formation (7). Previous studies also show that HP1 and H3K9me associate with a subset of loci on euchromatic regions, and they presumably serve to fine tune the level of gene transcription (8-10). One significant question that comes up is how the chromatin structure is dynamically regulated to impact expression of genes in complex neuronal processes, such as learning and memory. Our earlier study on chromatin domain mapping of chromosome 4 suggests that heterochromatic domains may be regulated by the activities of RNA polymerase II (RNAPII) complexes, which form a "barrier" to prevent heterochromatin spreading and transcriptional gene silencing (11). However, the mechanism underlying such a mode of regulation and the consequence on reprogrammed transcription remain to be investigated. ResultsCyclin-Dependent Kinase 12 ...

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Insight into the molecular mechanism of LINC00152/miR‐215/CDK13 axis in hepatocellular carcinoma progression

Wang

Zhang

et al. 2019

J of Cellular Biochemistry

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Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. Nevertheless, its underlying molecular mechanisms are largely unknown. LINC00152 are recently investigated in several cancer types. In our current investigation, we observed LINC00152 was obviously upregulated in HCC cells. LINC00152 was significantly downregulated by infecting LV‐shLINC00152 in HepG2 and SNU449 cells. Loss of LINC00152 remarkably repressed HCC cell proliferation, cell colony formation, induced cell apoptosis, and restrained cell migration/invasion. Growing evidence has reported long noncoding RNAs can sponge microRNAs to modulate cancer process. Here, we indicated miR‐215 was greatly decreased in HCC and LINC00152 regulated HCC development via sponging miR‐215. For another, the binding association between LINC00152 and miR‐215 was proved by a series of functional assays. CDK13 was predicted as the target of miR‐215. Upregulation of miR‐215 greatly depressed CDK13 in HCC cells. Subsequently, the in vivo results demonstrated that silence of LINC00152 restrained HCC development via modulating miR‐215 to up‐regulate CDK13. Therefore, it was revealed that LINC00152 contributed to the progression of HCC by the modulation of miR‐215 and CDK13.

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CDC2L5, a Cdk‐like kinase with RS domain, interacts with the ASF/SF2‐associated protein p32 and affects splicing in vivo

Cited by 55 publications

References 43 publications

Characterization of Cyclin L1 and L2 Interactions with CDK11 and Splicing Factors

Characterization of Cyclin L1 and L2 Interactions with CDK11 and Splicing Factors

Heterochromatin remodeling by CDK12 contributes to learning in Drosophila

Insight into the molecular mechanism of LINC00152/miR‐215/CDK13 axis in hepatocellular carcinoma progression

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