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)

Gene mutations provide valuable clues to cellular metabolism. In humans such insights come mainly from genetic disorders. Ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome (NBS) are two distinct but closely related, single gene disorders that highlight a complex junction of several signal transduction pathways. These pathways appear to control defense mechanisms against specific types of damage to cellular macromolecules, and probably regulate the processing of certain types of DNA damage or normal intermediates of DNA metabolism. A-T is characterized primarily by cerebellar degeneration, immunodeficiency, genome instability, clinical radiosensitivity, and cancer predisposition. NBS shares all these features except cerebellar deterioration. The cellular phenotypes of A-T and NBS are almost indistinguishable, however, and include chromosomal instability, radiosensitivity, and defects in cell cycle checkpoints normally induced by ionizing radiation. The recent identification of the gene responsible for A-T, ATM, has revealed its product to be a large, constitutively expressed phosphoprotein with a carboxy-terminal region similar to the catalytic domain of phosphatidylinositol 3-kinases (PI 3-kinases). ATM is a member of a family of proteins identified in various organisms, which share the PI 3-kinase domain and are involved in regulation of cell cycle progression and response to genotoxic agents. Some of these proteins, most notably the DNA-dependent protein kinase, have an associated protein kinase activity, and preliminary data indicate this activity in ATM as well. Mutations in A-T patients are null alleles that truncate or destabilize the ATM protein. Atm-deficient mice recapitulate the human phenotype with slower nervous-system degeneration. Two ATM interactors, c-Abl and p53, underscore its role in cellular responses to genotoxic stress. The complexity of ATM's structure and mode of action make it a paradigm of multifaceted signal transduction proteins involved in many physiological pathways via multiple protein-protein interactions. The as yet unknown NBS protein may be a component in an ATM-based complex, with a key role in sensing and processing specific DNA damage or intermediates and signaling their presence to the cell cycle machinery.
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PMID:Ataxia-telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart. 944 10

A 30-kb genomic segment containing the promoter and first 9 exons of PRKDC, the gene encoding the catalytic subunit (DNA-PKcs) of the human DNA-activated protein kinase, DNA-PK, was isolated and partially sequenced. Sequence comparison with the NCBI nonredundant database revealed the locations of the first 13 exons of the upstream gene, MCM4. MCM4 is an essential component of a protein complex that prevents DNA from being replicated more than once per cell cycle. The MCM4 and DNA-PKcs promoters are in CpG islands separated by approximately 700 bp, and transcription from each initiates at multiple, closely spaced sites. Both promoters lack TATA boxes, and the MCM4 promoter also lacks an initiator (Inr) element but has an inverted CCAAT box. The DNA-PKcs promoter has an Inr-like sequence as well as a downstream MED-1 element. The two promoters appear to function independently, as sequences required for core promoter activity do not overlap, and sequences extending into the 5' region of each gene had little or no effect on transcription of the other gene, as shown in transient transfection assays. The arrangement of the PRKDC/MCM4 gene pair is similar to that of the ATM/E14(NPAT) gene pair. ATM, the product of the gene mutated in ataxia telangiectasia, and DNA-PKcs function in pathways that detect or repair DNA damage and are members of a family of large, serine/threonine kinases that are closely related to phosphatidylinositol 3 kinases.
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PMID:The promoters for human DNA-PKcs (PRKDC) and MCM4: divergently transcribed genes located at chromosome 8 band q11. 946 98

The C-terminal part of the largest subunit of eukaryotic RNA polymerase II is composed solely of the highly repeated consensus sequence Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7. This domain, called the C-terminal domain (CTD), is phosphorylated mostly at serine residues during transcription initiation, but the precise role of this phosphorylation remains controversial. Several protein kinases are able to phosphorylate this sequence in vitro. The aim of this work was to define the positions of the amino acids phosphorylated by four of these CTD kinases (transcription factor (TF) IIH-kinase, DNA-dependent protein kinase, and the mitogen-activated protein kinases ERK1 and ERK2) and to compare the specificity of these different protein kinases. We show that TFIIH kinase and the mitogen-activated protein kinases phosphorylate only serine 5 of the CTD sequence, whereas DNA-dependent protein kinase phosphorylates serines 2 and 7. Among the different CTD kinases, only TFIIH kinase is appreciably more active on two repeats of the consensus sequence than on one motif. These in vitro results can provide some clues to the nature of the protein kinases responsible for the in vivo phosphorylation of the RNA polymerase CTD. In particular, the ratio of phosphorylated serine to threonine observed in vivo cannot be explained if TFIIH kinase is the only protein kinase involved in the phosphorylation of the CTD.
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PMID:Characterization of the residues phosphorylated in vitro by different C-terminal domain kinases. 950 78

The catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs) is a member of a sub-family of phosphatidylinositol (PI) 3-kinases termed PIK-related kinases. A distinguishing feature of this sub-family is the presence of a conserved C-terminal region downstream of a PI 3-kinase domain. Mutants defective in DNA-PKcs are sensitive to ionising radiation and are unable to carry out V(D)J recombination. Irs-20 is a DNA-PKcs-defective cell line with milder gamma-ray sensitivity than two previously characterised mutants, V-3 and mouse scid cells. Here we show that the DNA-PKcs protein from irs-20 cells can bind to DNA but is unable to function as a protein kinase. To verify the defect in irs-20 cells and provide insight into the function and expression of DNA-PKcs in double-strand break repair and V(D)J recombination we introduced YACs encoding human and mouse DNA-PKcs into defective mutants and achieved complementation of the defective phenotypes. Furthermore, in irs-20 we identified a mutation in DNA-PKcs that causes substitution of a lysine for a glutamic acid in the fourth residue from the C-terminus. This represents a strong candidate for the inactivating mutation and provides supportive evidence that the extreme C-terminal motif is important for protein kinase activity.
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PMID:Molecular and biochemical characterisation of DNA-dependent protein kinase-defective rodent mutant irs-20. 951 90

The DNA-dependent protein kinase (DNA-PK) is a heterotrimeric enzyme that binds to double-stranded DNA and is required for the rejoining of double-stranded DNA breaks in mammalian cells. It has been proposed that DNA-PK functions in this DNA repair pathway by binding to the ends of broken DNA molecules and phosphorylating proteins that bind to the damaged DNA ends. Another enzyme that binds to DNA strand breaks and may also function in the cellular response to DNA damage is the poly(ADP-ribose) polymerase (PARP). Here, we show that PARP can be phosphorylated by purified DNA-PK, and the catalytic subunit of DNA-PK is ADP-ribosylated by PARP. The protein kinase activity of DNA-PK can be stimulated by PARP in the presence of NAD+ in a reaction that is blocked by the PARP inhibitor 1, 5-dihydroxyisoquinoline. The stimulation of DNA-PK by PARP-mediated protein ADP-ribosylation occurs independent of the Ku70/80 complex. Taken together, these results show that PARP can modify the activity of DNA-PK in vitro and suggest that these enzymes may function coordinately in vivo in response to DNA damage.
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PMID:Stimulation of the DNA-dependent protein kinase by poly(ADP-ribose) polymerase. 960 59

The NFkB transcription factor is activated by diverse stimuli, including Ionizing Radiation (IR) and the cytokine TNF alpha. The role of DNA-PK, a protein kinase involved in the response to DNA damage, in the activation of NF kappa B by IR and TNF alpha was examined. In M059K cells, which express DNA-PK, NF kappa B was activated by both TNF alpha and IR. In M059J cells, which do not express DNA-PK, IR did not activate NF kappa B, whereas TNF alpha induction of NF kappa B was still observed. In HeLa cells, wortmannin, an inhibitor of DNA-PK, blocked the induction of NF kappa B by IR but not by TNF alpha. DNA-PK also phosphorylated the NF kappa B inhibitory proteins IkB-alpha and IkB-beta in vitro, and deletion analysis demonstrated that DNA-PK phosphorylates 2 distinct regions of IkB-beta. These results indicate that DNA-PK participates in the activation of NF kappa B by IR but not by TNF alpha.
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PMID:The DNA-dependent protein kinase participates in the activation of NF kappa B following DNA damage. 963 58

The role of the basal activity of the serine/threonine protein kinase, protein kinase C (PKC) in the regulation of anti-CD95-induced apoptosis in Jurkat T cells was investigated. The PKC-specific inhibitor GF 109203X and the proposed cPKC-specific inhibitor Go 6976, in a concentration-dependent manner, increased the percentage of cells undergoing apoptosis induced by anti-CD95 mAb as demonstrated by propidium iodide (PI) staining, TUNEL assay and DNA fragmentation by gel electrophoresis. Furthermore, Go 6976 and GF 109203X abrogated phorbol myristate acetate-induced inhibition of anti-CD95-induced apoptosis. To examine the molecular mechanism by which PKC modulates anti-CD95-induced apoptosis, the effects of Go 6976 on known effector and regulatory molecules of cell death were studied. Increased recruitment of cells undergoing apoptosis was associated with enhanced anti-CD95-induced proteolytic cleavage of the most receptor-proximal cysteine protease caspase-8, subsequent cleavage and activation of the machinery protease caspase-3, and cleavage of the caspase substrates DNA-dependent protein kinase catalytic subunit, poly-(ADP-ribose) polymerase and lamin B1. CD95 and FADD protein levels in Jurkat T cells were not altered by Go 6976 treatment. In addition, Go 6976 did not alter protein levels and subcellular distribution of the anti-apoptotic molecules Bcl-2 and Bcl-xL. These data suggest indirectly that basal PKC activity acts at an early stage in the anti-CD95-induced caspase pathway to attenuate subsequent activation of downstream effector molecules and associated apoptosis in Jurkat T cells.
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PMID:Inhibition of the protein kinase C pathway promotes anti-CD95-induced apoptosis in Jurkat T cells. 970 Oct 26

Ataxia telangiectasia-mutated gene (ATM) is a 350-kDa protein whose function is defective in the autosomal recessive disorder ataxia telangiectasia (AT). Affinity-purified polyclonal antibodies were used to characterize ATM. Steady-state levels of ATM protein varied from undetectable in most AT cell lines to highly expressed in HeLa, U2OS, and normal human fibroblasts. Subcellular fractionation showed that ATM is predominantly a nuclear protein associated with the chromatin and nuclear matrix. ATM protein levels remained constant throughout the cell cycle and did not change in response to serum stimulation. Ionizing radiation had no significant effect on either the expression or distribution of ATM. ATM immunoprecipitates from HeLa cells and the human DNA-dependent protein kinase null cell line MO59J, but not from AT cells, phosphorylated the 34-kDa subunit of replication protein A (RPA) complex in a single-stranded and linear double-stranded DNA-dependent manner. Phosphorylation of p34 RPA occurred on threonine and serine residues. Phosphopeptide analysis demonstrates that the ATM-associated protein kinase phosphorylates p34 RPA on similar residues observed in vivo. The DNA-dependent protein kinase activity observed for ATM immunocomplexes, along with the association of ATM with chromatin, suggests that DNA damage can induce ATM or a stably associated protein kinase to phosphorylate proteins in the DNA damage response pathway.
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PMID:Characterization of ATM expression, localization, and associated DNA-dependent protein kinase activity. 972 99

The yeast Ada and TBP class of Spt proteins interact in multiple complexes that are required for transcriptional regulation. We have identified Tra1p as a component of these complexes through tandem mass spectrometry analysis of proteins that associate with Ngg1p/Ada3p. TRA1 is an essential gene and encodes a 3744-amino acid protein that is a member of a group of proteins including the catalytic subunit of DNA-dependent protein kinase, ATM and TRRAP, with carboxyl-terminal regions related to phosphatidylinositol 3-kinases. The interaction between Tra1p and Ada/Spt components was verified by the reciprocal coimmunoprecipitation of Ada2p and Tra1p from whole cell extracts in one or more complexes containing Spt7p. Tra1p cofractionated with Ngg1p and Spt7p through consecutive chromatography on Mono Q, DNA-cellulose, and Superose 6 columns. Binding of Tra1p to DNA-cellulose required Ada components. The association of Tra1p with two Ada.Spt complexes was suggested by its cofractionation with Ngg1p and Spt7p in two peaks on the Mono Q column. In the absence of Ada2p, the elution profile of Tra1p shifted to a distinct peak. Despite the similarity of Tra1p to a group of putative protein kinases, we have not detected protein kinase activity within immunoprecipitates of Tra1p or the Ada.Spt complexes.
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PMID:Tra1p is a component of the yeast Ada.Spt transcriptional regulatory complexes. 975 93

To characterize further the function of the intracellular vitamin D receptor (VDR), we have developed stable transfectant variants of a vitamin D-responsive cell line (U937) which express either decreased or increased numbers of VDR. In this study we have analyzed changes in gene expression associated with this variable VDR expression. Initial experiments indicated that a 50% decrease in VDR levels was associated with a 2-fold increase in cell proliferation and a similar rise in c-myc mRNA expression. Further studies were carried out using differential RNA display (DD). Sequence analysis of DD products revealed two cDNAs with identity to known gene products: the catalytic sub-unit of DNA-protein kinase (DNA-PK(CS)), and the peroxisomal enzyme 17beta-hydroxysteroid dehydrogenase type IV (17beta-HSD IV). Northern analysis confirmed that expression of both mRNAs was reduced in cells with decreased numbers of VDR. Down-regulation of 17beta-HSD IV mRNA expression was associated with enhanced estradiol inactivation by U937 cells, suggesting a link between estrogenic pathways and cell proliferation. Further Northern analyses indicated that there was no significant change in 17beta-HSD IV or DNA-PK(CS) mRNA levels following treatment with 1,25(OH)2D3, although expression of both genes varied with changes in cell proliferation. These data suggest that, in addition to its established role as a hormone-dependent trans-activator, VDR may influence gene expression by ligand-independent mechanisms.
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PMID:Differential RNA display identifies novel genes associated with decreased vitamin D receptor expression. 978 9


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