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)

We describe the regulation of expression, activity and subcellular localization of a cell cycle control-related kinase, p58GTA, during the withdrawal from the cell cycle of U937 human leukemic cells induced by phorbol esters. Our studies indicate that steady-state mRNA, protein levels, transcription and subcellular localization of this kinase are affected in distinctly different manners by phorbol esters (phorbol 12-myristate 13-acetate, PMA). Steady-state mRNA levels increase dramatically within 1 h of PMA treatment, while steady-state protein levels increase only slightly. However, within 24 h of PMA treatment both steady-state p58GTA mRNA and protein levels decrease markedly. Assays of p58GTA protein kinase activity show that, even though steady-state protein levels are relatively constant, protein kinase activity increases within 30 min of PMA treatment, and then peaks at 2 h and 12 h after PMA treatment. Once again, p58GTA protein kinase activity decreases by 48 h to levels similar to unstimulated cells. These results suggest that the expression of the p58GTA protein kinase gene and, quite possibly, its post-translational modification are affected by phorbol esters in a complex manner.
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PMID:Regulation of the p58GTA cell division control-related protein kinase during phorbol 12-myristate 13-acetate-induced terminal differentiation of U937 cells. 154 64

Minimal ectopic expression of a 58-kDa protein kinase (PITSLRE beta 1), distantly related to members of the cdc2 gene family, induces telophase delay, abnormal chromosome segregation, and decreased growth rates in Chinese hamster ovary cells. Here we show that this decrease in cell growth rate is due to apoptosis. Apoptosis is also induced by ectopic expression of an amino-terminal deletion mutant containing the catalytic and C-terminal domains of PITSLRE beta 1 but not by other mutants lacking histone H1 kinase activity or by other members of the cdc2 gene family. However, unlike the wild-type PITSLRE beta 1 over-expressors, ectopic expression of the N-terminal PITSLRE beta 1 mutant does not result in telophase delay or abnormal chromosome segregation. These results suggested that the function of this protein kinase could be linked to apoptotic signaling. To test this hypothesis, we examined levels of PITSLRE mRNA, steady-state protein, and enzyme activity in human T cells undergoing apoptosis after activation with the anti-Fas monoclonal antibody (MAb). All were substantially elevated shortly after Fas MAb treatment. In addition to new transcription and translation, proteolysis contributed to the increased steady-state levels of a novel 50-kDa PITSLRE protein, as suggested by the diminution of larger PITSLRE isoforms observed in the same cells. Indeed, treatment of the Fas-activated T cells with a serine protease inhibitor prevented apoptotic death and led to the accumulation of larger, less active PITSLRE kinase isoforms but not the enzymatically active 50-kDa PITSLRE isoform. Finally, induction of apoptosis by glucocorticoids in the same cell line, as well as by Fas MAb treatment of another T-cell line, led to a similar induction of 50-kDa PITSLRE protein levels over time. These findings suggest that (i) PITSLRE kinase(s) may lie within apoptotic signaling pathway(s), (ii) serine protease activation may be an early event in Fas-activated apoptosis of human T cells, and (iii) some PITSLRE kinase isoforms may be targets of apoptotic proteases.
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PMID:PITSLRE protein kinase activity is associated with apoptosis. 752 24

p58cdc2L1, a protein kinase implicated in apoptotic signaling, is one of eight separate kinases encoded by three tandemly duplicated and linked genes, which we have termed PITSLRE A, B and C. One allele of this complex on chromosome 1 was either deleted or translocated in each of 18 neuroblastoma cell lines with cytogenetically apparent 1p alterations. A protein encoded by this locus, PITSLRE gamma 1, was absent in three of the lines and a smaller, apparently truncated, PITSLRE polypeptide was found in another line. These findings identify a novel gene complex on chromosome 1 that encodes a protein kinase subfamily. We suggest that the PITSLRE locus may harbour one or more tumour suppressor genes affected by chromosome 1p36 modifications in neuroblastoma.
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PMID:Alterations in the PITSLRE protein kinase gene complex on chromosome 1p36 in childhood neuroblastoma. 792 Jun 54

The p58 (PITSLRE beta 1) protein kinase (PK) is a member of a large supergene family related to the master mitotic protein kinase, p34cdc2. This PK is also a member of a sub-family itself, with at least six additional related PITSLRE PK isoforms expressed by alternative splicing and promoter utilization from three duplicated genes. Minimal overproduction of the PITSLRE beta 1 PK in Chinese hamster ovary cells results in a late mitotic delay, suggesting that this PK's function may be related to the cell cycle [Bunnell et al., Proc. Natl. Acad. Sci. USA 87 (1990) 7467-7471]. Further studies using structural and functional mutants have shown that PITSLRE PKs are involved in signaling apoptosis. The gene encoding the PITSLRE beta 1 PK has previously been isolated and structurally characterized [Eipers et al., Genomics 13 (1992) 613-621]. Here we characterize the minimal essential promoter for this gene. Analysis of a 1.18-kb stretch of DNA located upstream from the PITSLRE beta 1 start codon demonstrates that significant cat gene expression can be driven by a construct containing this sequence. Deletion studies of this DNA fragment have defined a minimal promoter that extends 144 bp 5' of the previously mapped transcription start point (tsp), and 521 bp 5' of the start codon. This region of PITSLRE beta 1 DNA does not contain canonical TATA-box sequences or G + C-rich sequences associated with many promoters, yet it has approximately 20% of the promoting activity when compared to the SV40 early promoter. This suggests that this DNA sequence is a relatively strong basal promoter of a previously uncharacterized type.
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PMID:Analysis of the 5' flanking sequences from the human protein kinase p58 (PITSLRE beta 1)-encoding gene. 805 43

The two genes encoding the PITSLRE protein kinase isoforms, CDC2L1 and CDC2L2, are localized to human chromosome band 1p36. The PITSLRE protein kinases are a part of the p34cdc2 supergene family. Several protein products of the CDC2L locus may be effector(s) in apoptotic signaling. The larger PITSLRE p110 isoforms appear to regulate some aspect of RNA splicing/transcription during the cell cycle. One or more of these genes may function as tumor suppressor genes in melanoma. Using fluorescence in situ hybridization, one allele of the CDC2L gene complex on chromosome 1 was either deleted or translocated in 8 of 14 different melanoma cell lines. We also observed mutations in the 5' promoter region of the CDC2L1 gene in four different cell lines relative to normal melanocytes using PCR-SSCP analysis and direct DNA sequencing. Western blot analysis revealed decreased level of PITSLRE protein expression in several cell lines, as well as in four surgical malignant melanoma specimens relative to normal melanocytes. Thus, the decreased PITSLRE protein expression appears to result from deletion of the CDC2L alleles and possibly by mutations within the 5' promoter region. We propose that aberrations in the CDC2L genes may contribute to the pathogenesis or progression of melanoma.
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PMID:Abnormalities in the p34cdc2-related PITSLRE protein kinase gene complex (CDC2L) on chromosome band 1p36 in melanoma. 1147 3

Our laboratories have documented a significantly high occurrence of chromosome 1p36 rearrangements in non-Hodgkin lymphoma (NHL). The cell division cycle 2-like 1(CDC2L1) (also known as TP58 or PITSLRE) gene, a protein kinase implicated in apoptotic signaling, is located at the very distal region of chromosome 1p36 and is likely to be disrupted by structural rearrangements involving 1p36. To determine the molecular consequences of the recurrent involvement of the 1p36 region, we examined metaphases containing 1p36 abnormalities from 31 specimens derived from 26 patients for the possible deletion of CDC2L1 by fluorescence in situ hybridization (FISH) using the TP58clk-1 DNA probe. Twenty-three cases exhibited the loss of CDC2L1 from the abnormal chromosome 1. In 2 of 26 cases, the gene locus was translocated to the partner chromosome, and in four specimens, all derived from one case, CDC2L1 was not deleted. This pilot investigation suggests that 1p36 rearrangements, and consequently the loss of the CDC2L1 gene locus, is important in NHL. This work also opens avenues for further molecular studies and prognostic correlations.
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PMID:Deletion of cell division cycle 2-like 1 gene locus on 1p36 in non-Hodgkin lymphoma. 997 38

The Cdc2L locus encoding the PITSLRE protein kinases maps to chromosome band 1p36 and consists of two duplicated and tandemly linked genes. The purpose of the present study was to determine whether diminution of PITSLRE kinases leads to deregulation of apoptosis. The human melanoma cell lines A375 (Cdc2L wild-type alleles) and UACC 1227 (mutant Cdc2L alleles) were tested with agonist anti-Fas monoclonal antibody. We found that exposure of these cells to anti-Fas for 24, 48, or 72 h resulted in differential sensitivity to Fas-induced apoptosis. In A375, cell death started at 24-48 h post-treatment, and it was maximal by 72 h. Conversely, UACC 1227 cells were resistant to Fas-mediated apoptosis. Induction of PITSLRE histone H1 kinase activity was observed in A375 anti-Fas treated but not in UACC 1227 cells. Also, the PITSLRE protein kinase activity in A375 anti-Fas-treated cells preceded maximal levels of apoptosis. Finally, fluorescence confocal microscopy revealed a nuclear localization of PITSLRE proteins in normal melanocytes and A375 cells but a cytoplasmic localization in UACC 1227 cells. The differences in PITSLRE protein and cellular localization between A375 and UACC 1227 cells appear to account for the differences in sensitivity of the two cells lines to anti-Fas and staurosporine. These observations suggest that alterations in PITSLRE gene expression and protein localization may result in the loss of apoptotic signaling.
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PMID:Fas-induced apoptosis in human malignant melanoma cell lines is associated with the activation of the p34(cdc2)-related PITSLRE protein kinases. 1049 14

Control of neuronal gene expression by drugs or neurotransmitters is a critical step in long-term neural plasticity. Here, we show that a gene induced in the striatum by cocaine or direct dopamine stimulation, ania-6, is a member of a novel family of cyclins with homology to cyclins K/T/H/C. Further, different types of neurotransmitter stimulation cause selective induction of distinct ania-6 isoforms, through alternative splicing. The longer Ania-6 protein colocalizes with nuclear speckles and is associated with key elements of the RNA elongation/processing complex, including the hyperphosphorylated form of RNA polymerase II, the splicing factor SC-35, and the p110 PITSLRE cyclin-dependent kinase. Distinct types of neuronal stimulation may therefore differentially modulate nuclear RNA processing, through altered transcription and splicing of ania-6.
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PMID:Dopamine and glutamate induce distinct striatal splice forms of Ania-6, an RNA polymerase II-associated cyclin. 1168 87

Although the PITSLRE protein kinases are members of the cyclin-dependent kinase superfamily, their cellular function is unclear. Previously we demonstrated that the general RNA splicing factor RNPS1 is a specific PITSLRE p110 kinase interactor in vivo. This suggests that the PITSLRE family of protein kinases is involved in some aspect of RNA processing or transcription. Here we identify multiple transcriptional elongation factors, including ELL2, TFIIF(1), TFIIS, and FACT, as PITSLRE kinase-associated proteins. We demonstrate that PITSLRE p110 protein kinases co-immunoprecipitate and/or co-purify with these elongation factors as well as with RNA polymerase II. Antibody-mediated inhibition of PITSLRE kinase specifically suppressed RNA polymerase II-dependent in vitro transcription initiated at a GC-rich (adenosine deaminase) or TATA box-dependent (Ad2ML) promoter, and this suppression was rescued by readdition of purified PITSLRE p110 kinase. Together, these data strongly suggest that PITSLRE protein kinases participate in a signaling pathway that potentially regulates or links transcription and RNA processing events.
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PMID:PITSLRE p110 protein kinases associate with transcription complexes and affect their activity. 1170 59

The PITSLRE protein kinases, hereafter referred to as cyclin-dependent kinase 11 (CDK11) due to their association with cyclin L, are part of large molecular weight protein complexes that contain RNA polymerase II (RNAP II) as well as numerous transcription and RNA processing factors. Data presented here demonstrate that the influence of CDK11(p110) on transcription and splicing does not involve phosphorylation of the RNAP II carboxyl-terminal domain by CDK11(p110). We have isolated a DRB- and heparin-sensitive protein kinase activity that co-purifies with CDK11(p110) after ion exchange and affinity purification chromatography. This protein kinase was identified as casein kinase 2 (CK2) by immunoblot and mass spectrometry analyses. In addition to the RNAP II carboxyl-terminal domain, CK2 phosphorylates the CDK11(p110) amino-terminal domain. These data suggest that CDK11(p110) isoforms participate in signaling pathways that include CK2 and that its function may help to coordinate the regulation of RNA transcription and processing events. Future experiments will determine how phosphorylation of CDK11(p110) by CK2 specifically affects RNA transcription and/or processing events.
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PMID:Casein kinase 2 interacts with cyclin-dependent kinase 11 (CDK11) in vivo and phosphorylates both the RNA polymerase II carboxyl-terminal domain and CDK11 in vitro. 1242 41


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