Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel method employing filter arrays of a cDNA expression library for the identification of substrates for protein kinases was developed. With this technique, we identified a new member of the cyclin family, cyclin L2, as a substrate of the nuclear protein kinase DYRK1A. Cyclin L2 contains an N-terminal cyclin domain and a C-terminal arginine/serine-rich domain (RS domain), which is a hallmark of many proteins involved in pre-mRNA processing. The gene for cyclin L2 encodes the full-length cyclin L2, which is predominantly expressed in testis, as well as a truncated splicing variant (cyclin L2S) that lacks the RS domain and is ubiquitously expressed in human tissues. Full-length cyclin L2, but not cyclin L2S, was associated with the cyclin-dependent kinase PITSLRE. Cyclin L2 interacted with splicing factor 2 in vitro and was co-localized with the splicing factor SC35 in the nuclear speckle compartment. Photobleaching experiments showed that a fusion protein of green fluorescent protein and cyclin L2 in nuclear speckles rapidly exchanged with unbleached molecules in the nucleus, similar to other RS domain-containing proteins. In striking contrast, the closely related green fluorescent protein-cyclin L1 was immobile in the speckle compartment. DYRK1A interacted with cyclin L2 in pull-down assays, and overexpression of DYRK1A stimulated phosphorylation of cyclin L2 in COS-7 cells. These data characterize cyclin L2 as a highly mobile component of nuclear speckles and suggest that DYRK1A may regulate splicing by phosphorylation of cyclin L2.
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PMID:Characterization of cyclin L2, a novel cyclin with an arginine/serine-rich domain: phosphorylation by DYRK1A and colocalization with splicing factors. 1462 75

The CDK11 (cyclin-dependent kinase 11, formerly known as PITSLRE) protein kinases are part of the large family of p34(cdc2)-related kinases and have been shown to play a role in cell cycle progression, RNA processing and apoptosis. They are encoded by two genes-cell division control like 1 (Cdc2L1) and cell division control like 2 (Cdc2L2). To date, little is known about the transcription factors controlling their expression. To understand the mechanisms underlying the regulation of CDK11 gene expression, we cloned and identified the Cdc2L2 promoter and determined its transcriptional regulatory elements. By deletion analysis, a region between nucleotides -145 and +10 was identified to be critical for basal level transcription of the Cdc2L2 gene. Sequencing analysis revealed that the proximal promoter of the Cdc2L2 gene is GC rich and does not contain TATA and CAAT boxes. However, multiple consensus and near consensus transcription factor binding sites were found to be present in this region, such as two Ets-1, one cAMP-responsive element (CRE) and one TCF11/LCR-F1/Nrf1 binding sites. Site-directed mutagenesis and transfection studies revealed that all these binding sites were necessary to achieve sustained transcriptional activity. Electrophoretic mobility shift assay confirmed that transcription factors Ets-1 and CREB bind to the Cdc2L2 promoter elements, indicating their potential role in the transcriptional regulation of Cdc2L2 gene. More importantly, Ets-1, CREB and phosphorylated CREB were found binding to the endogenous Cdc2L2 promoter using chromatin immunoprecipitation (CHIP) assay. Our results provide the foundation for further studies into the regulation of Cdc2L2 gene expression in normal homeostasis and cancer.
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PMID:Identification and characterization of the human Cdc2l2 gene promoter. 1508 26

CDK11p110 (cyclin-dependent kinase 11p110, formerly known as PITSLRE) is a member of the CDK superfamily. It associates with cyclin L and is involved in the regulation of transcription and in premRNA splicing. During staurosporine-, Fas- and tumour necrosis factor a-induced apoptosis, CDK11p110, is cleaved by caspases to generate smaller 46-50 kDa proteins containing the catalytic kinase domain. Ectopic expression of the caspase-processed form CDK11p46 induces apoptosis. The mechanisms that regulate activation and stability of CDK11 isoforms are still unclear. In the present study, we demonstrate that in human melanoma cells CDK11p110 and CDK11p46 interact with Hsp90 (heat-shock protein 90) and its co-chaperone cdc37. Furthermore, we show that the treatment of cells with the Hsp90-specific inhibitor geldanamycin leads to ubiquitination and enhanced degradation of both CDK11p110 and CDK11p46 through a proteasome-dependent pathway. We also determined that geldanamycin-triggered degradation of CDK11p46 slows down the progression of apoptosis. These results indicate that Hsp90 and cdc37 stabilize CDK11 kinase, and suggest that this stabilization is crucial for its pro-apoptotic function.
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PMID:Regulation of stability of cyclin-dependent kinase CDK11p110 and a caspase-processed form, CDK11p46, by Hsp90. 1534 6

CDK11 (cyclin-dependent kinase 11, formerly known as PITSLRE) is a member of the p34cdc2-related kinases. It has been previously shown to be involved in a variety of different cellular processes including RNA processing, apoptosis, and cell cycle progression. It is encoded by two different but highly similar genes, Cdc2L1 (cell division control 2 like 1) and Cdc2L2 (cell division control 2 like 2). Previous studies from our group identified and characterized the transcriptional regulation of the human Cdc2L2 gene promoter. The current studies identify and characterize the Cdc2L1 gene promoter. We cloned the promoter and elucidated the different transcriptional regulatory elements that reside within the 5' region of the gene. Deletion analysis of the promoter showed a region of nucleotides -152 to +11 to be necessary for basal transcription of the Cdc2L1 gene. Sequencing analysis found this region of the promoter to be highly GC-rich but is lacking both TATA and CAAT boxes. There are several different transcription factor binding sites that are consensus or near consensus found within this region. The potential binding sites include two Ets-1 sites, one Skn-1 site, and one E2F-1 site. Transfection studies of various site-directed mutagenesis clones for these different sites revealed that both Ets-1 sites play critical roles in sustained transcriptional activity as well as Skn-1. Chromatin immunoprecipitation of the endogenous promoter with Ets-1 and Skn-1 verified an in vivo association of Ets-1 and Skn-1 transcription factors with the endogenous promoter. These results, in addition to our Cdc2L2 results, lead to the further comprehension of the fundamental mechanisms dictating CDK11 gene expression through the Cdc2L1 gene promoter.
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PMID:Isolation and characterization of the human Cdc2L1 gene promoter. 1565 72

The caspase-processed cyclin-dependent kinase 11 (formerly known as PITSLRE) is implicated in apoptotic signaling. However, the mechanism of apoptotic signal transduction through CDK11(p46) is still unclear. We used a yeast two-hybrid screening strategy and identified NOT2 as an interacting partner of caspase-processed C-terminal kinase domain of CDK11 (CDK11(p46)). We demonstrate that CDK11(p46) directly interacts with NOT2 in vitro and in human cells. The NOT domain in the C-terminal part of NOT2 is responsible for the association between CDK11(p46) and NOT2. Both NOT2 and CDK11(p46) predominantly co-localized in the nucleus. Furthermore, we show that overexpression of NOT2 reduces luciferase mRNA and induces apoptosis. However, NOT2 is not phosphorylated by CDK11(p46). These findings suggest that CDK11 may contribute to apoptosis by regulating the activity of NOT2 independent of its kinase activity.
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PMID:The cyclin-dependent kinase 11 interacts with NOT2. 1603 7

CDK11 (cyclin-dependent kinase 11, formerly known as PITSLRE) is a serine/threonine kinase that associates with the cyclin L2 regulatory partner. CDK11 catalytic activity has been associated with apoptosis, transcription, and RNA processing. Here, we identify novel chicken testis CDK11 transcripts that differ in their 5'UTR, 3'UTR, splicing of the exon 6, and polyadenylation. We have also characterized the differential expression of CDK11 in somatic tissues, during testis development and upon testicular regression by diethylstilbestrol (DES) treatment. The heterogeneity of CDK11 transcripts presented in this study suggests new possibilities for post-transcriptional regulation.
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PMID:Diversification of CDK11 transcripts during chicken testis development and regression. 1609 71

Members of the Hedgehog (Hh) family of signaling proteins are powerful regulators of developmental processes in many organisms and have been implicated in many human disease states. Here we report the results of a genome-wide RNA interference screen in Drosophila melanogaster cells for new components of the Hh signaling pathway. The screen identified hundreds of potential new regulators of Hh signaling, including many large protein complexes with pleiotropic effects, such as the coat protein complex I (COPI) complex, the ribosome and the proteasome. We identified the multimeric protein phosphatase 2A (PP2A) and two new kinases, the D. melanogaster orthologs of the vertebrate PITSLRE and cyclin-dependent kinase-9 (CDK9) kinases, as Hh regulators. We also identified a large group of constitutive and alternative splicing factors, two nucleoporins involved in mRNA export and several RNA-regulatory proteins as potent regulators of Hh signal transduction, indicating that splicing regulation and mRNA transport have a previously unrecognized role in Hh signaling. Finally, we showed that several of these genes have conserved roles in mammalian Hh signaling.
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PMID:A genome-wide RNA interference screen in Drosophila melanogaster cells for new components of the Hh signaling pathway. 1631 96

14-3-3 proteins are crucial in a wide variety of cellular responses including cell cycle progression, DNA damage checkpoints and apoptosis. One particular 14-3-3 isoform, sigma, is a p53-responsive gene, the function of which is frequently lost in human tumours, including breast and prostate cancers as a result of either hypermethylation of the 14-3-3sigma promoter or induction of an oestrogen-responsive ubiquitin ligase that specifically targets 14-3-3sigma for proteasomal degradation. Loss of 14-3-3sigma protein occurs not only within the tumours themselves but also in the surrounding pre-dysplastic tissue (so-called field cancerization), indicating that 14-3-3sigma might have an important tumour suppressor function that becomes lost early in the process of tumour evolution. The molecular basis for the tumour suppressor function of 14-3-3sigma is unknown. Here we report a previously unknown function for 14-3-3sigma as a regulator of mitotic translation through its direct mitosis-specific binding to a variety of translation/initiation factors, including eukaryotic initiation factor 4B in a stoichiometric manner. Cells lacking 14-3-3sigma, in marked contrast to normal cells, cannot suppress cap-dependent translation and do not stimulate cap-independent translation during and immediately after mitosis. This defective switch in the mechanism of translation results in reduced mitotic-specific expression of the endogenous internal ribosomal entry site (IRES)-dependent form of the cyclin-dependent kinase Cdk11 (p58 PITSLRE), leading to impaired cytokinesis, loss of Polo-like kinase-1 at the midbody, and the accumulation of binucleate cells. The aberrant mitotic phenotype of 14-3-3sigma-depleted cells can be rescued by forced expression of p58 PITSLRE or by extinguishing cap-dependent translation and increasing cap-independent translation during mitosis by using rapamycin. Our findings show how aberrant mitotic translation in the absence of 14-3-3sigma impairs mitotic exit to generate binucleate cells and provides a potential explanation of how 14-3-3sigma-deficient cells may progress on the path to aneuploidy and tumorigenesis.
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PMID:14-3-3sigma controls mitotic translation to facilitate cytokinesis. 1736 Nov 71

(Macro)autophagy is a membrane-trafficking process that serves to sequester cellular constituents in organelles termed autophagosomes, which target their degradation in the lysosome. Autophagy operates at basal levels in all cells where it serves as a homeostatic mechanism to maintain cellular integrity. The levels and cargoes of autophagy can, however, change in response to a variety of stimuli, and perturbations in autophagy are known to be involved in the aetiology of various human diseases. Autophagy must therefore be tightly controlled. We report here that the Drosophila cyclin-dependent kinase PITSLRE is a modulator of autophagy. Loss of the human PITSLRE orthologue, CDK11, initially appears to induce autophagy, but at later time points CDK11 is critically required for autophagic flux and cargo digestion. Since PITSLRE/CDK11 regulates autophagy in both Drosophila and human cells, this kinase represents a novel phylogenetically conserved component of the autophagy machinery.
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PMID:The cyclin-dependent kinase PITSLRE/CDK11 is required for successful autophagy. 2180 50

In response to a variety of neural damages in the CNS, quiescent astrocytes become reactive astrocytes. Astrocytes are the major glial subtype and are important effectors that participate in the pathogenesis of numerous neural disorders, including trauma, stroke, aging, and developmental, genetic, idiopathic or acquired neurodegenerative diseases. CDK11(p58) (Cyclin-dependent kinases 11 protein 58/PITSLRE) is a p34cdc2-related protein kinase that plays an important role in normal cell cycle progression. In the process of LPS stimulus, the expression of CDK11(p58) in astrocytes was increased. Induced CDK11(p58) was parallel to astrocyte inflammatory response. Knockdown of CDK11(p58) by small-interfering RNAs (siRNAs) reduced the LPS-induced astrocyte inflammatory response, while overexpression CDK11(p58) enhanced the process. CDK11(p58) exerted its functions via activating p38 and JNK MAPK pathways. This study delineates that CDK11(p58) may be a significant regulatory factor for host defenses in central nervous system (CNS) inflammation.
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PMID:CDK11(p58) promotes rat astrocyte inflammatory response via activating p38 and JNK pathways induced by lipopolysaccharide. 2212 Jun 54


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