A New Subfamily of High Molecular Mass CDC2-Related Kinases with PITAI/VRE Motifs

Marquès, François; Moreau, Jean‐Luc; Peaucellier, Gérard; Lozano, Jean-Claude; Schatt, Philippe; Picard, André; Callebaut, Isabelle; Perret, Eric; Genevière, Anne-Marie

doi:10.1006/bbrc.2000.4042

Cited by 38 publications

(37 citation statements)

References 20 publications

(14 reference statements)

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“…It is possible that CDK11 p110 regulates alternative splicing in the same manner as CDK12, and by acting with CDK11 p110 the overexpressed cyclin L1␣ protein may still be able to change the splicing pattern even in the absence of CDK12. The protein sequence of human CDK12 is very similar to that of a recently identified kinase, CDC2L5 (22). There is 92% amino acid identity in the kinase domain and 52% identity overall between human CDK12 L and human CDC2L5.…”

Section: Discussionmentioning

confidence: 73%

“…Like CDK12, CDC2L5 contains an RS domain at the aminoterminal region. It has thus been suggested that these two genes belong to a new subfamily in the CDC2-like protein kinase family (22). In view of the structural similarity between CDK12 and CDC2L5, it is likely that CDC2L5 may interact with cyclin L1 or a related cyclin(s) and regulate RNA processing.…”

Section: Discussionmentioning

confidence: 99%

“…The CDK12 gene is located on human chromosome 17q12 (AC009283) and on mouse chromosome 11 (AL591205). The closest homologous protein to human CDK12 is human CDC2L5 (22), which also contains a CDC2-like protein kinase domain and an RS domain.…”

Section: Cloning and Sequence Analysis Of Cdk12mentioning

confidence: 99%

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Identification and Characterization of the CDK12/Cyclin L1 Complex Involved in Alternative Splicing Regulation

Chen¹,

Wang²,

Fann

2006

Molecular and Cellular Biology

127

105

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CrkRS is a Cdc2-related protein kinase that contains an arginine-and serine-rich (SR) domain, a characteristic of the SR protein family of splicing factors, and is proposed to be involved in RNA processing. However, whether it acts together with a cyclin and at which steps it may function to regulate RNA processing are not clear. Here, we report that CrkRS interacts with cyclin L1 and cyclin L2, and thus rename it as the long form of cyclin-dependent kinase 12 (CDK12 L ). A shorter isoform of CDK12, CDK12 S , that differs from CDK12 L only at the carboxyl end, was also identified. Both isoforms associate with cyclin L1 through interactions mediated by the kinase domain and the cyclin domain, suggesting a bona fide CDK/cyclin partnership. Furthermore, CDK12 isoforms alter the splicing pattern of an E1a minigene, and the effect is potentiated by the cyclin domain of cyclin L1. When expression of CDK12 isoforms is perturbed by small interfering RNAs, a reversal of the splicing choices is observed. The activity of CDK12 on splicing is counteracted by SF2/ASF and SC35, but not by SRp40, SRp55, and SRp75. Together, our findings indicate that CDK12 and cyclin L1/L2 are cyclin-dependent kinase and cyclin partners and regulate alternative splicing.It is estimated that fewer than 30,000 genes are present in the human genome (13). The heterogeneity generated by this number of genes is not enough to account for the complexity that specifies human organs. One way to create more proteomic variations is through alternative splicing (2, 21). About 38 to 74% of human genes are subject to alternative splicing (3,14,15), and mutations that affect splicing patterns are the underlying causes of some cancers and neurodegenerative diseases (10, 29). It is estimated that ϳ15% of disease-causing mutations in human genes involve misregulation of alternative splicing (25). Thus, unraveling the pathways and the molecules involved in alternative splicing is crucial to an understanding of various intricate cellular functions and for the management of human diseases.Although cyclin-dependent kinases (CDKs) and their associated cyclins are pivotal for cell cycle progression and RNA transcription (23), evidence has emerged that they also engage in the regulation of RNA splicing (19,27). For example, CDK11 p110 colocalizes with the general splicing factor RNPS1 (20) and serine-and arginine-rich (SR) proteins, such as 9G8 (12). Moreover, depletion of CDK11 p110 immune complex impedes the efficiency of an in vitro splicing assay (12). Similarly, blocking the activity of cyclin L1, a cyclin partner of CDK11 p110 , inhibits the second step (cutting of the lariat-exon intermediate and ligation of adjacent exons) of pre-mRNA splicing in an in vitro assay (7).A recently identified Cdc2-related kinase, CrkRS, is also implicated in the regulation of RNA splicing (16). CrkRS contains an arginine-and serine-rich (RS) domain, a characteristic found in the SR protein family of splicing factors. Furthermore, CrkRS localizes in nuclear speckles and CrkRS-immun...

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Identification and Characterization of the CDK12/Cyclin L1 Complex Involved in Alternative Splicing Regulation

Chen¹,

Wang²,

Fann

2006

Molecular and Cellular Biology

127

105

View full text Add to dashboard Cite

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“…Considering the known biological functions of the deleted genes, CDC2L5, which encodes a cyclin-dependent kinase, may be the most likely target, because this gene family is involved in cell cycle and gene expression regulation. 30 Alternatively, the deletion may cause deregulation of a gene in the vicinity of the breakpoints, for example, the RALA gene. It is noteworthy that it has been reported that activation of RALA is necessary for RAS-induced tumorigenesis.…”

Section: Gli3mentioning

confidence: 99%

High-resolution genome-wide array-based comparative genome hybridization reveals cryptic chromosome changes in AML and MDS cases with trisomy 8 as the sole cytogenetic aberration

et al. 2006

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“…This motif is involved in the binding of a CDK to a cyclin and has been used to classify other newly identified CDK-related kinases, such as PCTAIRE, PITSLRE, PFTAIRE, PITAIRE, KKI-ALRE, PISSLRE, MAK, and MRK, etc. (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). The function of these CDK-related kinases has not been fully understood.…”

mentioning

confidence: 99%

Functional characterization of human PFTK1 as a cyclin-dependent kinase

Shu

Yan

et al. 2007

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

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Cyclin-dependent kinases (CDKs) are crucial regulators of the eukaryotic cell cycle whose activities are controlled by associated cyclins. PFTK1 shares limited homology to CDKs, but its ability to associate with any cyclins and its biological functions remain largely unknown. Here, we report the functional characterization of human PFTK1 as a CDK. PFTK1 specifically interacted with cyclin D3 (CCND3) and formed a ternary complex with the cell cycle inhibitor p21 Cip1 in mammalian cells. We demonstrated that the kinase activity of PFTK1 depended on CCND3 and was negatively regulated by p21 Cip1 . Moreover, we identified the tumor suppressor Rb as a potential downstream substrate for the PFTK1/CCND3 complex. Importantly, knocking down PFTK1 expression by using siRNA caused cell cycle arrest at G1, whereas ectopic expression of PFTK1 promoted cell proliferation. Taken together, our data strongly suggest that PFTK1 acts as a CDK that regulates cell cycle progression and cell proliferation.cyclin D3 ͉ p21 ͉ retinoblastoma ͉ cell cycle

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A New Subfamily of High Molecular Mass CDC2-Related Kinases with PITAI/VRE Motifs

Cited by 38 publications

References 20 publications

Identification and Characterization of the CDK12/Cyclin L1 Complex Involved in Alternative Splicing Regulation

Identification and Characterization of the CDK12/Cyclin L1 Complex Involved in Alternative Splicing Regulation

High-resolution genome-wide array-based comparative genome hybridization reveals cryptic chromosome changes in AML and MDS cases with trisomy 8 as the sole cytogenetic aberration

Functional characterization of human PFTK1 as a cyclin-dependent kinase

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