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)

Cyclin A is regulated primarily through transcription control during the mammalian cell cycle. A dual mechanism of cyclin A transcriptional repression involves, on the one hand, promoter-bound inhibitory complexes of E2F transcription factors and RB (retinoblastoma) family proteins, and on the other, chromatin-directed histone deacetylase activity that is recruited to the cyclin A promoter early in the cell cycle in association with these RB proteins. This dual regulation maintains transcriptional silence of the cyclin A locus until its transcription is required in S-phase. At that time, RB family members dissociate from E2F proteins and nucleosomal restructuring of the locus takes place, to permit transcriptional activation and resultant S-phase progression to proceed. We have identified a double bromo-domain-containing protein Brd2, which exhibits apparent 'scaffold' or transcriptional adapter functions and mediates recruitment of both E2F transcription factors and chromatin-remodelling activity to the cyclin A promoter. We have shown previously that Brd2-containing nuclear, multiprotein complexes contain E2F-1 and -2. In the present study, we show that, in S-phase, they also contain histone H4-directed acetylase activity. Overexpression of Brd2 in fibroblasts accelerates the cell cycle through increased expression of cyclin A and its associated cyclin-dependent kinase activity. Chromatin immunoprecipitation studies show that Brd2 is physically present at the cyclin A promoter and its overexpression promotes increased histone H4 acetylation at the promoter as it becomes transcriptionally active, suggesting a new model for the dual regulation of cyclin A.
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PMID:Bromodomain analysis of Brd2-dependent transcriptional activation of cyclin A. 1554 37

Our studies examining the role of the cell cycle-regulated kinase cyclin A/Cdk2 in progesterone receptor (PR) action have demonstrated that cyclin-dependent kinase activity is required for PR function and that cyclin A/Cdk2 functions as a PR coactivator. Although Cdk2 can phosphorylate PR, elimination of these phosphorylation sites has little effect on the ability of cyclin A/Cdk2 to stimulate PR activity. PR interacts with cyclin A and recruits cyclin A/Cdk2 to progestin-responsive promoters, stimulating transcription. Inhibition of Cdk2 activity abolishes progesterone-dependent activation of PR target genes in part through inhibition of PR-dependent recruitment of steroid receptor coactivator 1 (SRC-1) and subsequent histone H4 acetylation at the target promoter. In vitro studies revealed that the interaction between SRC-1 and PR is dependent upon phosphorylation of SRC-1. This heretofore-unknown mechanism provides a potential means for integrating the regulation of PR activity with cell cycle progression. Moreover, the ability of PR to recruit cyclin A/Cdk2 to target promoters provides locally elevated levels of kinase, which can preferentially facilitate phosphorylation-dependent interactions and enzymatic activities of coactivators at the target promoter.
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PMID:Cyclin-dependent kinase activity is required for progesterone receptor function: novel role for cyclin A/Cdk2 as a progesterone receptor coactivator. 1560 48

Distinct patterns of posttranslational histone modifications can regulate DNA-templated events such as mitosis, transcription, replication, apoptosis, and DNA damage, suggesting the presence of a "histone code" in these nuclear processes. Phosphorylation of histone H2A S129 at sites of DNA double-strand breaks (DSBs) has been implicated in damage repair in yeast. Here, we describe another phosphorylation event on serine 1 (S1) of histone H4; this event is also associated with MMS- or phleomycin-induced DSBs but not with UV-induced DNA damage. Chromatin-immunoprecipitation (ChIP) studies of an HO-endonuclease-inducible strain show that S1 phosphorylation is specifically enhanced 20- to 25-fold in nucleosomes proximal to the DSB. In addition, we show that casein kinase II (CK2) can phosphorylate H4 S1 in vitro and that null or temperature-sensitive CK2 yeast mutants are defective for induction of H4 S1 phosphorylation upon DNA damage in vivo. Furthermore, H4 S1 phosphorylation and CK2 play a role in DSB re-joining as indicated by a nonhomologous end-joining (NHEJ) plasmid assay. CK2 has been implicated in regulating a DNA-damage response; our data suggest that histone H4 S1 is one of its physiological substrates. These data suggest that this modification is a part of the DNA-repair histone code.
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PMID:Phosphorylation of histone H4 serine 1 during DNA damage requires casein kinase II in S. cerevisiae. 1582 38

The NuA4 complex is a histone H4/H2A acetyltransferase involved in transcription and DNA repair. While histone acetylation is important in many processes, it has become increasingly clear that additional histone modifications also play a crucial interrelated role. To understand how NuA4 action is regulated, we tested various H4 tail peptides harboring known modifications in HAT assays. While dimethylation at arginine 3 (R3M) had little effect on NuA4 activity, phosphorylation of serine 1 (S1P) strongly decreased the ability of the complex to acetylate H4 peptides. However, R3M in combination with S1P alleviates the repression of NuA4 activity. Chromatin from cells treated with DNA damage-inducing agents shows an increase in phosphorylation of serine 1 and a concomitant decrease in H4 acetylation. We found that casein kinase 2 phosphorylates histone H4 and associates with the Rpd3 deacetylase complex, demonstrating a physical connection between phosphorylation of serine 1 and unacetylated H4 tails. Chromatin immunoprecipitation experiments also link local phosphorylation of H4 with its deacetylation, during both transcription and DNA repair. Time course chromatin immunoprecipitation data support a model in which histone H4 phosphorylation occurs after NuA4 action during double-strand break repair at the step of chromatin restoration and deacetylation. These findings demonstrate that H4 phospho-serine 1 regulates chromatin acetylation by the NuA4 complex and that this process is important for normal gene expression and DNA repair.
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PMID:Regulation of NuA4 histone acetyltransferase activity in transcription and DNA repair by phosphorylation of histone H4. 1613 7

The cellular responses to double-stranded breaks (DSBs) typically involve the extensive accumulation of checkpoint proteins in chromatin surrounding the damaged DNA. One well-characterized example involves the checkpoint protein Crb2 in the fission yeast Schizosaccharomyces pombe. The accumulation of Crb2 at DSBs requires the C-terminal phosphorylation of histone H2A (known as gamma-H2A) by ATM family kinases in chromatin surrounding the break. It also requires the constitutive methylation of histone H4 on lysine-20 (K20). Interestingly, neither type of histone modification is essential for the Crb2-dependent checkpoint response. However, H4-K20 methylation is essential in a crb2-T215A strain that lacks a cyclin-dependent kinase phosphorylation site in Crb2. Here we explain this genetic interaction by describing a previously overlooked effect of the crb2-T215A mutation. We show that crb2-T215A cells are able to initiate but not sustain a checkpoint response. We also report that gamma-H2A is essential for the DNA damage checkpoint in crb2-T215A cells. Importantly, we show that inactivation of Cdc2 in gamma-H2A-defective cells impairs Crb2-dependent signaling to the checkpoint kinase Chk1. These findings demonstrate that full Crb2 activity requires phosphorylation of threonine-215 by Cdc2. This regulation of Crb2 is independent of the histone modifications that are required for the hyperaccumulation of Crb2 at DSBs.
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PMID:Cooperative control of Crb2 by ATM family and Cdc2 kinases is essential for the DNA damage checkpoint in fission yeast. 1631 98

The histone deacetylase inhibitors (HDA-CIs) butyrate and trichostatin A activate gamma-globin expression via a p38 mitogen-activating protein kinase (MAPK)-dependent mechanism. We hypothesized that down-stream effectors of p38 MAPK, namely activating transcription factor-2 (ATF-2) and cyclic AMP response element (CRE) binding protein (CREB), are intimately involved in fetal hemoglobin induction by these agents. In this study, we observed increased ATF-2 and CREB1 phosphorylation mediated by the HDACIs in K562 cells, in conjunction with histone H4 hyperacetylation. Moreover, enhanced DNA-protein interactions occurred in the CRE in the (G)gamma-globin promoter (G-CRE) in vitro after drug treatments; subsequent chromatin immunoprecipitation assay confirmed ATF-2 and CREB1 binding to the G-CRE in vivo. Enforced expression of ATF-2 and CREB produced (G)gamma-promoter trans-activation which was abolished by a 2-base pair mutation in the putative G-CRE. The data presented herein demonstrate that gamma-gene induction by butyrate and trichostatin A involves ATF-2 and CREB1 activation via p38 MAPK signaling.
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PMID:Mechanism for fetal hemoglobin induction by histone deacetylase inhibitors involves gamma-globin activation by CREB1 and ATF-2. 1689 60

In addition to its function as a cyclin-dependent kinase (cdk) inhibitor, p21waf1 fulfills additional roles involved in DNA replication and transcriptional regulation that could also contribute to cell cycle arrest. In this study, we have shown that p21waf1 functions as a transcriptional repressor of the myc and cdc25A genes. Ectopic expression of the cell cycle inhibitor down-modulates myc and cdc25A transcription but has no effect on cdk4 levels. Using chromatin immunoprecipitation, we found that p21waf1 is recruited to the promoters of these two genes together with the STAT3 and E2F1 transcription factors. Its presence on DNA is associated with an inhibition of the recruitment of the p300 histone acetylase and with a down-regulation of histone H4 acetylation. The same effect was also observed following DNA damage because topoisomerase inhibitors such as sn38 or doxorubicin also induce the association of p21waf1 with DNA. Following transcriptional repression of the myc and cdc25A genes, cells were arrested in the fraction with 4 N DNA content. By contrast, the expression of these two genes remains elevated in the absence of the cell cycle inhibitor, and p21waf1-/- cells re-replicate their DNA and become polyploid. In light of these results, we propose that p21waf1 simultaneously targets cdk and transcriptional regulators to prevent the expression of oncogenic pathways upon DNA damage.
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PMID:The cell cycle inhibitor p21waf1 binds to the myc and cdc25A promoters upon DNA damage and induces transcriptional repression. 1692 15

Controlled release of membrane-tethered, dormant precursors is an intriguing activation mechanism that regulates diverse cellular functions in eukaryotes. An exquisite example is the proteolytic activation of membrane-bound transcription factors. The proteolytic cleavage liberates active transcription factors from the membranes that can enter the nucleus and evokes rapid transcriptional responses to incoming stimuli. Here, we show that a membrane-bound NAC (for NAM, ATAF1/2, CUC2) transcription factor, designated NTM1 (for NAC with transmembrane motif1), is activated by proteolytic cleavage through regulated intramembrane proteolysis and mediates cytokinin signaling during cell division in Arabidopsis thaliana. Cell proliferation was greatly reduced in an Arabidopsis mutant with retarded growth and serrated leaves in which a transcriptionally active NTM1 form was constitutively expressed. Accordingly, a subset of cyclin-dependent kinase (CDK) inhibitor genes (the KIP-related proteins) was induced in this mutant with a significant reduction in histone H4 gene expression and in CDK activity. Consistent with a role for NTM1 in cell cycling, a Ds element insertional mutant was morphologically normal but displayed enhanced hypocotyl growth with accelerated cell division. Interestingly, cytokinins were found to regulate NTM1 activity by controlling its stability. These results indicate that the membrane-mediated activation of NTM1 defines a molecular mechanism by which cytokinin signaling is tightly regulated during cell cycling.
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PMID:A membrane-bound NAC transcription factor regulates cell division in Arabidopsis. 1709 12

Cell cycle progression beyond the G1/S phase transition requires the activation of a transcription complex containing histone nuclear factor P (HiNF-P) and nuclear protein mapped to ataxia telangiectasia (p220(NPAT)) in response to cyclin dependent kinase 2 (CDK2)/cyclin E signaling. We show here that the potent co-activating properties of HiNF-P/p220(NPAT) on the histone H4 gene promoter, which are evident in the majority of human cell types, are sporadically neutralized in distinct somatic cell lines. In cells where HiNF-P and p220(NPAT) do not activate the H4 gene promoter, HiNF-P instead represses transcription. Our data suggest that the cell type specific expression of the cyclin-dependent kinase inhibitory (CKI) protein p57(KIP2) inhibits the HiNF-P dependent activation of the histone H4 promoter. We propose that, analogous to E2F proteins and other cell cycle regulatory proteins, HiNF-P is a bifunctional transcriptional regulator that can activate or repress cell cycle controlled genes depending on the cellular context.
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PMID:HiNF-P is a bifunctional regulator of cell cycle controlled histone H4 gene transcription. 1716 57

Cyclic-AMP stimulation of GTP cyclohydrolase I (GCH1) gene transcription was investigated in PC12 cells, the protein kinase A-deficient PC12 cell line 126-1B2 and C6 cells using transient transfection assays of proximal promoter reporter constructs and wild type or dominant negative proteins, chromatin immunoprecipitation and real-time quantitative PCR. These studies show that protein kinase A is necessary and sufficient for cAMP-dependent transcription conferred by both the cAMP regulatory element and the adjacent CCAAT-box. In intact cells these cis-elements were shown to bind cAMP response element binding protein, CCAAT-enhancer binding protein beta and nuclear factor-Y, with each protein controlling a different aspect of the cAMP response. Cyclic-AMP acting through protein kinase A stimulated promoter recruitment of CCAAT-enhancer binding protein beta, nuclear factor-Y and RNA polymerase II while depleting the promoter of cyclic-AMP response element binding protein. Stimulation of transcription by cAMP was not associated with increased acetylation of histones H3 and H4 at proximal promoter nucleosomes, indicating that histone acetyltransferases are not involved in this response. Nonetheless, pharmacological inhibition of histone deacetylase activity did increase histone H4 acetylation and the recruitment of RNA polymerase II, indicating that histone acetyltransferases are normally associated with the proximal promoter. Only in C6 cells, however, did inhibition of histone deacetylases stimulate transcription and synergize with cAMP. These experiments provide the first glimpse of the GCH1 gene promoter functioning within intact cells and supply evidence for the involvement of histone acetyltransferase-containing complexes in GCH1 gene transcription.
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PMID:Protein kinase A-dependent recruitment of RNA polymerase II, C/EBP beta and NF-Y to the rat GTP cyclohydrolase I proximal promoter occurs without alterations in histone acetylation. 1739 55


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