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)

The pocket protein family of tumor suppressors, and Rb specifically, have been implicated as controlling terminal differentiation in many tissues, including the heart. To establish the biological functions of Rb in the heart and overcome the early lethality caused by germ line deletion of Rb, we used a Cre/loxP system to create conditional, heart-specific Rb-deficient mice. Mice that are deficient in Rb exclusively in cardiac myocytes (CRbL/L) are born with the expected Mendelian distribution, and the adult mice displayed no change in heart size, myocyte cell cycle distribution, myocyte apoptosis, or mechanical function. Since both Rb and p130 are expressed in the adult myocardium, we created double-knockout mice (CRbL/L p130-/-) to determine it these proteins have a shared role in regulating cardiac myocyte cell cycle progression. Adult CRbL/L p130-/- mice demonstrated a threefold increase in the heart weight-to-body weight ratio and showed increased numbers of bromodeoxyuridine- and phosphorylated histone H3-positive nuclei, consistent with persistent myocyte cycling. Likewise, the combined deletion of Rb plus p130 up-regulated myocardial expression of Myc, E2F-1, and G1 cyclin-dependent kinase activities, synergistically. Thus, Rb and p130 have overlapping functional roles in vivo to suppress cell cycle activators, including Myc, and maintain quiescence in postnatal cardiac muscle.
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PMID:Overlapping roles of pocket proteins in the myocardium are unmasked by germ line deletion of p130 plus heart-specific deletion of Rb. 1574 40

The vitamin K analog menadione (K3), capable of both redox cycling and arylating nucleophilic substrates by Michael addition, has been extensively studied as a model stress-inducing quinone in both cell culture and animal model systems. Exposure of keratin 8 (k-8) expressing human breast cancer cells (MCF7, T47D, SKBr3) to K3 (50-100 microM) induced rapid, sustained, and site-specific k-8 serine phosphorylation (pSer73) dependent on signaling by a single mitogen activated protein kinase (MAPK) pathway, MEK1/2. Normal nuclear morphology and k-8 immunofluorescence coupled with the lack of DNA laddering or other features of apoptosis indicated that K3-induced cytotoxicity, evident within 4 h of treatment and delayed but not prevented by MEK1/2 inhibition, was due to a form of stress-activated cell death known as oncosis. Independent of MAPK signaling was the progressive appearance of K3-induced cellular fluorescence, principally nuclear in origin and suggested by in vitro fluorimetry to have been caused by K3 thiol arylation. Imaging by UV transillumination of protein gels containing nuclear extracts from K3-treated cells revealed a prominent 17-kDa band shown to be histone H3 by immunoblotting and mass spectrometry (MS). K3 arylation of histones in vitro followed by electrospray ionization-tandem MS analyses identified the unique Cys110 residue within H3, exposed only in the open chromatin of transcriptionally active genes, as a K3 arylation target. These findings delineate new pathways associated with K3-induced stress and suggest a potentially novel role for H3 Cys110 as a nuclear stress sensor.
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PMID:Vitamin K3 (menadione)-induced oncosis associated with keratin 8 phosphorylation and histone H3 arylation. 1593 99

Although histone acetylation is important for epigenetic gene transcription, histone acetylation regulation by extracellular cues has rarely been evidenced. Here, we examined whether and how histone acetylation is regulated by cell adhesion-mediated signaling. Gastric carcinoma cells in suspension showed a higher histone acetylation, compared with fibronectin-adherent cells. This difference was supported by a decreased histone deacetylases activity. Furthermore, trichostatin A (TSA)-mediated histone acetylation was significantly increased only in suspended, but not in fibronectin-adherent, cells. Pharmacological inhibition of intracellular contractility-related myosin light chain kinase or RhoA-kinase (ROCK) or expression of ROCK1 small interfering RNA, dominant negative RhoA, or active Rac1 decreased basal and TSA-mediated histone H3 acetylations in suspended cells,whereas inhibition of calmodulin-dependent protein kinase II or transient overexpression of wild type myosin light chain kinase enhanced the acetylations. Meanwhile, chromatin immunoprecipitation showed higher basal and TSA-enhanced associations of ROCK1 promoter regions with Lys(9)-acetylated histone 3 in suspended cells than in fibronectin-adherent cells and expression of ROCK1 was higher and further increased by TSA treatment in suspension. In addition, phosphorylation of myosin light chain was further increased by TSA in suspension and higher in anchorage-independent cells over adherently growing cells, indicating an inverse relationship between ROCK1 expression-mediated contractility and cell adhesion abilities. Cell adhesion analysis showed that pharmacological activation of intracellular contractility-related signaling activities decreased cell adhesion abilities, whereas inhibition of them increased the adhesion. Taken together, these observations suggest that cell adhesion-related signal transduction regulates histone acetylation, presumably through a close functional linkage between intracellular contractility and histone deacetylases activity/histone acetylation.
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PMID:Cell adhesion status-dependent histone acetylation is regulated through intracellular contractility-related signaling activities. 1596 94

The Aurora kinase family is a well-characterized serine/threonine protein kinase family that regulates different processes of mitotic events. Although functions of animal and yeast Aurora kinases have been analyzed, plant aurora kinases were not identified and characterized. We identified three Aurora kinase orthologs in Arabidopsis thaliana and designated these as AtAUR1, AtAUR2, and AtAUR3. These AtAURs could phosphorylate serine 10 in histone H3, in vitro. Dynamic analyses of GFP-fused AtAUR proteins revealed that AtAUR1 and AtAUR2 localized at the nuclear membrane in interphase and located in mitotic spindles during cell division. AtAUR1 also localized in the cell plates. AtAUR3 showed dot-like distribution on condensed chromosomes at prophase and then localized at the metaphase plate. At late anaphase, AtAUR3 is evenly localized on chromosomes. The localization of AtAUR3 during mitosis is very similar to that of phosphorylated histone H3. Interestingly, an overexpression of AtAUR3 induces disassembly of spindle microtubules and alteration of orientation of cell division. Our results indicate that plant Aurora kinases have different characters from that of Aurora kinases of other eukaryotes.
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PMID:Characterization of plant Aurora kinases during mitosis. 1602 12

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 c-myb proto-oncogene product (c-Myb) regulates proliferation and differentiation of hematopoietic cells. Recently we have shown that c-Myb is degraded in response to Wnt-1 stimulation via a pathway involving TAK1 (TGF-beta-activated kinase), HIPK2 (homeodomain-interacting protein kinase 2), and NLK (Nemo-like kinase). NLK and HIPK2 bind directly to c-Myb and phosphorylate c-Myb at multiple sites, inducing its ubiquitination and proteasome-dependent degradation. The mammalian myb gene family contains two members in addition to c-myb, A-myb, and B-myb. Here, we report that the Wnt-NLK pathway also inhibits A-Myb activity, but by a different mechanism. As in the case of c-Myb, both NLK and HIPK2 bound directly to A-Myb and inhibited its activity. NLK phosphorylated A-Myb, but did not induce A-Myb degradation. Overexpression of NLK inhibited the association between A-Myb and the coactivator CBP, thus, blocking A-Myb-induced trans-activation. The kinase activity of NLK is required for the efficient inhibition of the association between A-Myb and CBP, although the kinase-negative form of NLK also partly inhibits the interaction between A-Myb and CBP. Furthermore, NLK induced the methylation of histone H3 at lysine-9 at A-Myb-bound promoter regions. Thus, the Wnt-NLK pathway inhibits the activity of each Myb family member by different mechanisms.
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PMID:The Wnt-NLK signaling pathway inhibits A-Myb activity by inhibiting the association with coactivator CBP and methylating histone H3. 1605

Menin, the product of the Men1 gene mutated in familial multiple endocrine neoplasia type 1 (MEN1), regulates transcription in differentiated cells. Menin associates with and modulates the histone methyltransferase activity of a nuclear protein complex to activate gene expression. However, menin-dependent histone methyltransferase activity in endocrine cells has not been demonstrated, and the mechanism of endocrine tumor suppression by menin remains unclear. Here, we show that menin-dependent histone methylation maintains the in vivo expression of cyclin-dependent kinase (CDK) inhibitors to prevent pancreatic islet tumors. In vivo expression of CDK inhibitors, including p27 and p18, and other cell cycle regulators is disrupted in mouse islet tumors lacking menin. Chromatin immunoprecipitation studies reveal that menin directly associates with regions of the p27 and p18 promoters and increases methylation of lysine 4 (Lys-4) in histone H3 associated with these promoters. Moreover, H3 Lys-4 methylation associated with p27 and p18 is reduced in islet tumors from Men1 mutant mice. Thus, H3 Lys-4 methylation is a crucial function of menin in islet tumor suppression. These studies suggest an epigenetic mechanism of tumor suppression: by promoting histone modifications, menin maintains transcription at multiple loci encoding cell cycle regulators essential for endocrine growth control.
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PMID:Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. 1619 83

To date, several classes of enzymes have been shown to affect transcription by catalyzing the modifications of nucleosomes via methylation. Employing our global proteomic screen, GPS, we have determined that the loss of Bur2, a component of the Bur1/Bur2 cyclin-dependent protein kinase, results in a decrease in histone H3(K4) methylation catalyzed by COMPASS. Furthermore, Bur1/Bur2 is required for histone H2B monoubiquitination by Rad6/Bre1. The effect on histone monoubiquitination and methylation is the result of defective Bur1/Bur2-mediated phosphorylation of Rad6 on its serine residue 120 and proper recruitment of the Paf1 complex to chromatin. We have also demonstrated that serine 120 of Rad6 is required for histone H2B monoubiquitination and the regulation of gene expression in vivo. Our results identify in vivo substrates for Bur1/Bur2, thus linking its role to transcriptional elongation and demonstrating a potential activation mechanism for histone H2B monoubiquitination by the Rad6/Bre1 complex.
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PMID:The Bur1/Bur2 complex is required for histone H2B monoubiquitination by Rad6/Bre1 and histone methylation by COMPASS. 1630 22

BUR1 and BUR2 encode the catalytic and regulatory subunits of a cyclin-dependent protein kinase complex that is essential for normal growth and has a general role in transcription elongation. To gain insight into its specific role in vivo, we identified mutations that reverse the severe growth defect of bur1Delta cells. This selection identified mutations in SET2, which encodes a histone methylase that targets lysine 36 of histone H3 and, like BUR1, has a poorly characterized role during transcription elongation. This genetic relationship indicates that SET2 activity is required for the growth defect observed in bur1Delta strains. This SET2-dependent growth inhibition occurs via methylation of histone H3 on lysine 36, since a methylation-defective allele of SET2 or a histone H3 K36R mutation also suppressed bur1Delta. We have explored the relationship between BUR1 and SET2 at the biochemical level and find that histone H3 is monomethylated, dimethylated, and trimethylated on lysine 36 in wild-type cells, but trimethylation is significantly reduced in bur1 and bur2 mutant strains. A similar methylation pattern is observed in RNA polymerase II C-terminal domain truncation mutants and in an spt16 mutant strain. Chromatin immunoprecipitation assays reveal that the transcription-dependent increase in trimethylated K36 over open reading frames is significantly reduced in bur2Delta strains. These results establish links between a regulatory protein kinase and histone methylation and lead to a model in which the Bur1-Bur2 complex counteracts an inhibitory effect of Set2-dependent histone methylation.
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PMID:The BUR1 cyclin-dependent protein kinase is required for the normal pattern of histone methylation by SET2. 1658 78

Follicle-stimulating hormone (FSH) is necessary and sufficient to induce maturation of ovarian follicles to a mature, preovulatory phenotype in the intact animal, resulting in the generation of mature eggs and production of estrogen. FSH accomplishes these actions by inducing a complex pattern of gene expression in target granulosa cells that is regulated by input from many different signaling cascades, including those for the extracellular regulated kinases (ERKs), p38 mitogen-activated protein kinases (MAPKs), and phosphatidylinositol-3 kinase (PI3K). The upstream kinase that appears to be responsible for initiating all of the signaling that regulates gene expression in these epithelial cells is protein kinase A (PKA). PKA not only signals to directly phosphorylate transcription factors like cAMP response element binding protein and to promote chromatin remodeling by phosphorylating histone H3, this versatile kinase also enhances the activity of the p38 MAPK, ERK, and PI3K pathways. Additionally, accumulating evidence suggests that activation of a single signaling cascade downstream of PKA is not sufficient to activate target gene expression. Rather, cross-talk between and among signaling cascades is required. We will review the signaling cascades activated by FSH in granulosa cells and how these cascades contribute to the regulation of select target gene expression.
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PMID:FSH signaling pathways in immature granulosa cells that regulate target gene expression: branching out from protein kinase A. 1661 57


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