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)

In all systems examined so far, the G2/M phase transition is controlled by the M-phase promoting factor (MPF), a complex of cdc2 (CDK1) and cyclin B1. Histone H1 kinase activity and MPF components are present in pachytene spermatocytes (PS). However, it has not been demonstrated yet that direct inhibition of MPF activity prevents the G2/M transition in these cells. When roscovitine, a potent inhibitor of CDK1, CDK2, and CDK5 activities, was added to cocultures of PS with Sertoli cells, the number of both secondary spermatocytes and round spermatids formed were lower than in control cultures, despite similar cell viability. This effect of roscovitine was reversible, did not involve the Sertoli cells, and was dependent on the concentration of the inhibitor. Roscovitine did not modify the amount of MPF in these germ cells but inhibited the CDK1- or CDK2-associated histone H1 kinase activity of PS. Hence a functional relationship between cyclin-dependent kinase activity and the spontaneous processing of the first meiotic division and, for the first time, of the second meiotic division of male germ cells is shown.
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PMID:Key role for cyclin-dependent kinases in the first and second meiotic divisions of rat spermatocytes. 1469 6

Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl groups from lysine residues of histone and nonhistone proteins. Recent studies suggest that they are key regulators of many cellular events, including cell proliferation and cancer development. Human class I HDACs possess homology to the yeast RPD3 protein and include HDAC1, HDAC2, HDAC3, and HDAC8. While HDAC1, HDAC2, and HDAC3 have been characterized extensively, almost nothing is known about HDAC8. Here we report that HDAC8 is phosphorylated by cyclic AMP-dependent protein kinase A (PKA) in vitro and in vivo. The PKA phosphoacceptor site of HDAC8 is Ser(39), a nonconserved residue among class I HDACs. Mutation of Ser(39) to Ala enhances the deacetylase activity of HDAC8. In contrast, mutation of Ser(39) to Glu or induction of HDAC8 phosphorylation by forskolin, a potent activator of adenyl cyclase, decreases HDAC8's enzymatic activity. Remarkably, inhibition of HDAC8 activity by hyperphosphorylation leads to hyperacetylation of histones H3 and H4, suggesting that PKA-mediated phosphorylation of HDAC8 plays a central role in the overall acetylation status of histones.
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PMID:Negative regulation of histone deacetylase 8 activity by cyclic AMP-dependent protein kinase A. 1470 48

Tumor progression due to loss of autocrine negative transforming growth factor-beta (TGF-beta) activity was reported in various cancers of epithelial origin. Estrogen receptor expressing (ER(+)) breast cancer cells are refractory to TGF-beta effects and exhibit malignant behavior due to loss or inadequate expression of TGF-beta receptor type II (RII). The exogenous TGF-beta effects on the modulation of cell cycle machinery were analyzed previously. However, very little is known regarding the endogenous control of cell cycle progression by autocrine TGF-beta. In this study, we have used a tetracycline regulatable RII cDNA expression vector to demonstrate that RII replacement reconstitutes autocrine negative TGF-beta activity in ER(+) breast cancer cells as evidenced by the delayed entry into S phase by the RII transfectants. Reversal of the delayed entry into S phase by the RII transfectants in the presence of tetracycline in addition to the decreased steady state transcription from a promoter containing the TGF-beta responsive element (p3TP-Lux) by TGF-beta neutralizing antibody treatment of the RII transfected cells confirmed that autocrine-negative TGF-beta activity was induced in the transfectants. Histone H1 kinase assays indicated that the delayed entry of RII transfectants into phase was associated with markedly reduced cyclin-dependent kinase (CDK)2 kinase activity. This reduction in kinase activity was due to the induction of CDK inhibitors p21/waf1/cip1 and p27/kip, and their association with CDK2. Tetracycline treatment of RII transfectants led to the suppression of p21/waf1/cip1and p27/kip expression, thus, directly demonstrating induction of CDK inhibitors by autocrine TGF-beta leading to growth control of ER(+) breast cancer cells.
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PMID:Endogenous control of cell cycle progression by autocrine transforming growth factor beta in breast cancer cells. 1505 6

Histone acetylation is an important epigenetic modification implicated in the regulation of chromatin structure and, subsequently, gene expression. Global histone deacetylation was reported in mouse oocytes during meiosis but not mitosis. The regulation of this meiosis-specific deacetylation has not been elucidated. Here, we demonstrate that p34(cdc2) kinase activity and protein synthesis are responsible for the activation of histone deacetylases and the inhibition of histone acetyltransferases (HATs), respectively, resulting in deacetylation of histone H4 at lysine-12 (H4K12) during mouse oocyte meiosis. Temporal changes in the acetylation state of H4K12 were examined immunocytochemically during meiotic maturation using an antibody specific for acetylated H4K12. H4K12 was deacetylated during the first meiosis, temporarily acetylated around the time of the first polar body (PB1) extrusion, and then deacetylated again during the second meiosis. Because these changes coincided with the known oscillation pattern of p34(cdc2) kinase activity, we investigated the involvement of the kinase in H4K12 deacetylation. Roscovitine, an inhibitor of cyclin-dependent kinase activity, prevented H4K12 deacetylation during both the first and second meiosis, suggesting that p34(cdc2) kinase activity is required for deacetylation during meiosis. In addition, cycloheximide, a protein synthesis inhibitor, also prevented deacetylation. After PB1 extrusion, at which time H4K12 had been deacetylated, H4K12 was re-acetylated in the condensed chromosomes by treatment with cycloheximide but not with roscovitine. These results demonstrate that HATs are present but inactivated by newly synthesized protein(s) that is (are) not involved in p34(cdc2) kinase activity. Our results suggest that p34(cdc2) kinase activity induces the deacetylation of H4K12 and that the deacetylated state is maintained by newly synthesized protein(s) that inhibits HAT activity during meiosis.
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PMID:Regulation of histone acetylation during meiotic maturation in mouse oocytes. 1529 24

Histone H1 of most eukaryotes is phosphorylated during the cell cycle progression and seems to play a role in the regulation of chromatin structure, affecting replication and chromosome condensation. In trypanosomatids, histone H1 lacks the globular domain and is shorter when compared with the histone of other eukaryotes. We have previously shown that in Trypanosoma cruzi, the agent of Chagas' disease, histone H1 is phosphorylated and this increases its dissociation from chromatin. Here, we demonstrate using mass spectrometry analysis that T. cruzi histone H1 is only phosphorylated at the serine 12 in the sequence SPKK, a typical cyclin-dependent kinase site. We also found a correlation between the phosphorylation state of histone H1 and the cell cycle. Hydroxyurea and lactacystin, which, respectively, arrest parasites at the G1/S and G2/M stages of the cell cycle, increased the level of histone H1 phosphorylation. Cyclin-dependent kinase-related enzymes TzCRK3, and less intensely the TzCRK1 were able to phosphorylate histone H1 in vitro. Histone H1 dephosphorylation was prevented by treating the parasites with okadaic acid but not with calyculin A. These findings suggest that T. cruzi histone H1 phosphorylation is promoted by cyclin dependent kinases, present during S through G2 phase of the cell cycle, and its dephosphorylation is promoted by specific phosphatases.
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PMID:Trypanosoma cruzi histone H1 is phosphorylated in a typical cyclin dependent kinase site accordingly to the cell cycle. 1569 89

Trypanosoma evansi contains protein kinases capable of phosphorylating endogenous substrates with apparent molecular masses in the range between 20 and 205 kDa. The major phosphopolypeptide band, pp55, was predominantly localized in the particulate fraction. Anti-alpha and anti-beta tubulin monoclonal antibodies recognized pp55 by Western blot analyses, suggesting that this band corresponds to phosphorylated tubulin. Inhibition experiments in the presence of emodin, heparin, and 2,3-bisphosphoglycerate indicated that the parasite tubulin kinase was a casein kinase 2 (CK2)-like activity. GTP, which can be utilized instead of ATP by CK2, stimulated rather than inactivated the phosphorylation of tubulin in the parasite homogenate and particulate fraction. However, GTP inhibited the cytosolic CK2 responsible for phosphorylating soluble tubulin and other soluble substrates. Casein and two selective peptide substrates, P1 (RRKDLHDDEEDEAMSITA) for casein kinase (CK1) and P2 (RRRADDSDDDDD) for CK2, were recognized as substrates in T. evansi. While the enzymes present in the soluble fraction predominantly phosphorylated P1, P2 was preferentially labeled in the particulate fractions. These results demonstrated the existence of CK1-like and CK2-like activities primarily located in the parasite cytosolic and membranous fractions, respectively. Histone II-A and kemptide (LRRASVA) also behaved as suitable substrates, implying the existence of other Ser/Thr kinases in T. evansi. Cyclic AMP only increased the phosphorylation of histone II-A and kemptide in the cytosol, demonstrating the existence of soluble cAMP-dependent protein kinase-like activities in T. evansi. However, no endogenous substrates for this enzyme were identified in this fraction. Further evidences were obtained by using PKI (6-22), a reported inhibitor of the catalytic subunit of mammalian cAMP-dependent protein kinases, which specifically hindered the cAMP-dependent phosphorylation of histone II-A and kemptide in the parasite soluble fraction. Since the sum of the values obtained in the parasite cytosolic and particulate fractions were always higher than the values observed in the total T. evansi lysate, the kinase activities examined here appeared to be inhibited in the original extract.
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PMID:Identification of casein kinase 1, casein kinase 2, and cAMP-dependent protein kinase-like activities in Trypanosoma evansi. 1576 1

Histone-lysine methylation is linked to transcriptional regulation and the control of epigenetic inheritance. Lysine residues can be mono-, di-, or trimethylated, and it has been suggested that each methylation state of a given lysine may impart a unique biological function. In yeast, histone H3 lysine 4 (K4) is mono-, di-, and trimethylated by the Set1 histone methyltransferase. Previous studies show that Set1 associates with RNA polymerase II and demarcates transcriptionally active genes with K4 trimethylation. To determine whether K4 trimethylation might be selectively regulated, we screened a library of yeast deletion mutants associated with transcriptional regulation and chromatin function. We identified BUR2, a cyclin for the Bur1/2 (BUR) cyclin-dependent protein kinase, as a specific regulator of K4 trimethylation. Surprisingly, BUR also regulated H2B monoubiquitylation, whereas other K4 methylation states and H3 lysine 79 (K79) methylation were unaffected. Synthetic genetic array (SGA) and transcription microarray analyses of a BUR2 mutant revealed that BUR is functionally similar to the PAF, Rad6, and Set1 complexes. These data suggest that BUR acts upstream of these factors to control their function. In support, we show that recruitment of the PAF elongation complex to genes is significantly impaired in a BUR2 deletion. Our data reveal a novel function for the BUR kinase in transcriptional regulation through the selective control of histone modifications.
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PMID:BUR kinase selectively regulates H3 K4 trimethylation and H2B ubiquitylation through recruitment of the PAF elongation complex. 1604 Feb 46

The initiation of DNA replication is tightly regulated in eukaryotic cells to ensure that the genome is precisely duplicated once and only once per cell cycle. This is accomplished by controlling the assembly of a prereplicative complex (pre-RC) which involves the sequential binding to replication origins of the origin recognition complex (ORC), Cdc6/Cdc18, Cdt1, and the minichromosome maintenance complex (Mcm2-Mcm7, or Mcm2-7). Several mechanisms of pre-RC regulation are known, including ATP utilization, cyclin-dependent kinase levels, protein turnover, and Cdt1 binding by geminin. Histone acetylation may also affect the initiation of DNA replication, but at present neither the enzymes nor the steps involved are known. Here, we show that Hbo1, a member of the MYST histone acetyltransferase family, is a previously unrecognized positive regulatory factor for pre-RC assembly. When Hbo1 expression was inhibited in human cells, Mcm2-7 failed to associate with chromatin even though ORC and Cdc6 loading was normal. When Xenopus egg extracts were immunodepleted of Xenopus Hbo1 (XHbo1), chromatin binding of Mcm2-7 was lost, and DNA replication was abolished. The binding of Mcm2-7 to chromatin in XHbo1-depleted extracts could be restored by the addition of recombinant Cdt1.
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PMID:Regulation of replication licensing by acetyltransferase Hbo1. 1642 61

Histone deacetylases (HDACs) are enzymes that regulate the functions of histones as well as nonhistones by catalyzing the removal of acetyl groups from lysine residues. HDACs regulate many biological processes, including the cell division cycle and tumorigenesis. Although recent studies have implicated HDAC8 in tumor cell proliferation, the molecular mechanisms linking HDAC8 to cell growth remain unknown. Here, we report that the human ortholog of the yeast ever-shorter telomeres 1B (EST1B) binds HDAC8. This interaction is regulated by protein kinase A-mediated HDAC8 phosphorylation and protects human EST1B (hEST1B) from ubiquitin-mediated degradation. Phosphorylated HDAC8 preferentially recruits Hsp70 to a complex that inhibits the CHIP (C-terminal heat shock protein interacting protein) E3 ligase-mediated degradation of hEST1B. Importantly, HDAC8 regulation of hEST1B protein stability modulates total telomerase enzymatic activity. Our findings reveal a novel mechanism by which HDAC8 contributes to tumorigenesis by regulating telomerase activity.
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PMID:Histone deacetylase 8 safeguards the human ever-shorter telomeres 1B (hEST1B) protein from ubiquitin-mediated degradation. 1680 64

Adenosine-to-inosine RNA editing has been recently implicated in the pathogenesis of inflammation through the upregulation of the editase adenosine deaminase acting on RNA 1 (ADAR1). Because cell proliferation is a key feature of the inflammatory process, the present study tested the hypothesis that overexpression of ADAR1 accelerates cell cycle. To that end, human embryonic kidney 293 cells were transiently transfected with ADAR1 or vector, and cell cycle was evaluated by fluorescence-activated cell sorter. Overexpression of wild-type ADAR1 decreased the proportion of G0-G1 cells (-19%, P<0.01, n=3), increased the percentage of S phase cells (+19%, P<0.01, n=3), and did not change the ratio of cells residing in the G2-M phase (n=3). This finding was supported by three observations. First, there was a parallel production in ADAR1-transfected cells of cyclin-dependent kinase (Cdk) 2 and cyclin A, a pivotal protein complex upregulated at the G1-S phase checkpoint, and of [p]-Histone H1, a marker of Cdk2 activity (+102%, P<0.01, n=3). Second, ADAR1-transfected cells displayed higher activity of the proliferation marker, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide. Third, using anti-ADAR1 antibody, direct binding of ADAR1 to Cdk2 messenger RNA was demonstrated in ADAR1-transfected cells by protein-RNA cross-linking and immunoprecipitation (+974%, P<0.01, n=3). Finally, causal relationships between ADAR1 and Cdk2 were confirmed by a study with the Cdk2 inhibitor, kenpaullone, which prevented the ADAR1-induced shift from the G0-G1 to the S phase. Taken together, these data show that ADAR1 increases cell cycle by shifting cells from the G0-G1 to the S phase through the upregulation of Cdk2.
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PMID:Adenosine deaminase acting on RNA 1 accelerates cell cycle through increased translation and activity of cyclin-dependent kinase 2. 1722 99


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