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)

Treatment of cells with agents that damage DNA leads to the induction of numerous genes. Recent studies aimed at understanding the events preceding the transcriptional activation of some of these DNA damage-inducible genes in mammalian cells have demonstrated that various extranuclear protein kinases are involved in the signaling cascades. The mammalian GADD153 gene, a member of the CCAAT enhancer-binding protein family of transcription factors, is highly induced by a variety of DNA-damaging agents as well as by certain growth arrest conditions and oxidative stresses. We have examined the effects of numerous protein kinase and phosphatase inhibitors on the DNA damage-induced expression of GADD153, to identify the signal transduction components involved in its transcriptional regulation. In contrast to the transcriptional activation of c-jun and collagenase in response to DNA damage, GADD153 induction involves neither protein kinase C nor tyrosine kinases but does appear to require an unidentified serine-threonine-kinase. Elevation of intracellular glutathione levels by treatment with N-acetylcysteine did not affect the methyl methanesulfonate-induced expression of the GADD153 gene, although it did diminish cadmium chloride-induced expression. These findings suggest that oxidative stress and DNA damage regulate GADD153 transcription through different pathways. Based on our findings and those of others with respect to other DNA damage-inducible genes, we propose a model depicting the complex pathways which appear to be involved in the regulation of mammalian genes in response to genotoxic stress and in which the DNA damage-induced expression of GADD153 represents a unique pathway independent of either protein kinase C or tyrosine kinase.
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PMID:The pathway regulating GADD153 induction in response to DNA damage is independent of protein kinase C and tyrosine kinases. 813 9

We have evaluated the role of various protein kinases on the induction of the gadd (growth arrest and DNA damage inducible) genes, using a panel of protein kinase inhibitors. Our data indicate that three different stress response pathways mediating gadd gene induction are most likely regulated by different protein kinases or combinations of protein kinases. The protein kinase inhibitor staurosporine and the temperature sensitive (ts) p34cdc2 mutant reduced induction by the alkylating agent methylmethane sulfonate (MMS) of the rodent gadd45 and gadd153 genes. However, staurosporine had no effect of the ionizing radiation (IR) induction of the human GADD45. Caffeine and 2-aminopurine, on the other hand, completely blocked this IR induction. Suramin, an antitumor drug that interferes with the interaction of growth factors with their receptors, inhibited the UV radiation induction of GADD45 and GADD153 but had no effect on the MMS and IR pathways. Elevated expression of gadd45 by medium depletion (starvation) was partially reduced by the addition of either genistein or tyrphostin, two protein tyrosine kinase inhibitors, while gadd153 was affected by tyrphostin only. Two inhibitors acting preferentially on cAMP-dependent protein kinase (PKA), N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide, HCl (H8) and protein kinase inhibitor (PKI), also had a moderate effect on the medium depletion-induced levels of both gadd genes. Thus, these varied effects of inhibitors on gadd gene responses point to important differences in the pathways controlling these responses.
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PMID:Evidence for distinct kinase-mediated pathways in gadd gene responses. 958 58

The breast and ovarian cancer susceptibility gene product BRCA1 has been reported to be expressed in a cell cycle-dependent manner; possess transcriptional activity; associate with several proteins, including the p53 tumor suppressor; and play an integral role in certain types of DNA repair. We show here that ectopic expression of BRCA1 using an adenovirus vector (Ad-BRCA1) leads to dephosphorylation of the retinoblastoma protein accompanied by a decrease in cyclin-dependent kinase activity. Flow cytometric analysis on Ad-BRCA1-infected cells revealed a G(1) or G(2) phase accumulation. High density cDNA array screening of colon, lung, and breast cancer cells identified several genes affected by BRCA1 expression in a p53-independent manner, including DNA damage response genes and genes involved in cell cycle control. Notable changes included induction of the GADD45 and GADD153 genes and a reduction in cyclin B1 expression. Therefore, BRCA1 has the potential to modulate the expression of genes and function of proteins involved in cell cycle control and DNA damage response pathways.
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PMID:BRCA1 effects on the cell cycle and the DNA damage response are linked to altered gene expression. 1064 42

Changes in gene expression within the hippocampus induced by denervation after electrolytic fimbria-fornix lesion in rat were compared to morphological and biochemical alterations. Fimbria-fornix lesion results in degeneration of hippocampal cholinergic terminals as evidenced by a sustained (2 days to 1 month) decrease in cholineacetyltransferase (ChAT) activity (50%). These changes were accompanied by a decrease in growth associated protein 43 (GAP-43) immunoreactivity in all hippocampal layers 4 days after lesion followed by a subsequent increase and return to normal levels by 20 days postinjury. This increase in GAP-43 expression in the hippocampus between 7 to 20 days after lesion may reflect heterotypic sprouting. TUNEL-positive cells were revealed by in situ assay within the hippocampus at 10 days, but not at 3 days, after lesion. Two subtracted cDNA libraries from the dorsal hippocampus of control and injured rats (at 3 and 10 days postlesion) were constructed in order to search for new genes potentially implicated in degeneration/regeneration phenomena. We analysed 1,536 clones from each library by differential screening and found a total of 46 up-regulated genes. Among the 15 known genes, 6 coded for proteins involved in signal transduction pathways. The upregulation of growth arrest DNA damage induced gene (GADD153), brain-specific RING finger protein, JNK interacting protein (JIP-1), protein kinase A (PKA), and Na+K+ ATPase was studied by quantitative polymerase chain reaction (PCR). Two of these genes, GADD153 and JIP-1, have been previously shown to participate in cell modifications induced by stress and apoptosis.
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PMID:Up-regulation of genes involved in cellular stress and apoptosis in a rat model of hippocampal degeneration. 1065 Aug 79

Supernumerary ring chromosomes varying with respect to both size and number were found as the primary cytogenetic anomaly in a rare benign soft tissue chondroma resected from the floor of the mouth of a 3-year-old girl. Reverse fluorescence in situ hybridization paint probes prepared by polymerase chain reaction from microdissected rings produced fluorescent signal over two large but discontinuous parts of the chromosome 12 long arm, subdivided into four regions. This case expands the spectrum of mesenchymal neoplasms in which ring chromosomes have been described as the primary genetic anomaly. A review of the literature reporting similar findings in other soft tissue tumors further supports the possibility that low-level amplification of chromosome 12 long-arm regions may contribute to abnormal cellular proliferation in a variety of mesenchymal tumors. Genes implicated in the control of the cell cycle such as sarcoma amplified sequence (SAS), the human homolog of the murine double-minute type 2 gene (MDM-2), proto-oncogenes CHOP/GADD153, GLI, A2MR, cyclin-dependent kinase (CDK4), and the high mobility group (HMGIC) gene implicated in mesenchymal tumorigenesis are all located on the long arm of chromosome 12. Chromosomal abnormalities involving the 12q13-q15 region are associated with a wide range of benign soft tissue tumors and sarcomas.
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PMID:Supernumerary ring chromosomes derived from the long arm of chromosome 12 as the primary cytogenetic anomaly in a rare soft tissue chondroma. 1074 95

The CAAT/enhancer binding protein homologous transcription factor CHOP, also known as GADD153, is involved in DNA damage, growth arrest, and the induction of apoptosis after endoplasmic reticulum stress and nutrient deprivation. CHOP dimerizes with and inhibits the binding of C/EBP-related transcription factors to their consensus DNA target sequences and also forms novel complexes with other transcriptional proteins (e.g. c-Jun, c-Fos). The transcriptional activation of these complexes is modified by their phosphorylation. Phosphorylation of CHOP at serine 79 and serine 81 by p38-MAP kinase enhances its transcriptional activity. Here we show that an interactive association between CHOP and casein kinase II (CK2) results in the phosphorylation of its amino-terminal transactivation domain. Mapping of the functional domains of CHOP indicates that the region in CHOP required for association with CK2 differs from that required for its phosphorylation. Th binding of CK2 to CHOP requires only the carboxylterminal bZip domain of CHOP, whereas phosphorylation involves residues located in the amino-terminal domain. The presence of the bZip domain, however, facilitates the phosphorylation of CHOP. Analyses of the effect of point mutations of CHOP on its transcriptional activity and the effect of specific inhibitors of CK2 lead us to conclude that CK2-mediated phosphorylation of CHOP inhibits its transcriptional activity. Our findings suggest that inhibition of the proapoptotic functions of CHOP by CK2 may be a mechanism by which CK2 prevents apoptosis and promotes cellular proliferation.
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PMID:CHOP transcription factor phosphorylation by casein kinase 2 inhibits transcriptional activation. 1287 86

Protein ubiquitination and subsequent degradation by the proteasome are important mechanisms regulating cell cycle, growth and differentiation, and apoptosis. Recent studies in cancer therapy suggest that drugs that disrupt the ubiquitin/proteasome pathway induce apoptosis and sensitize malignant cells and tumors to conventional chemotherapy. In this study we addressed the role of phosphorylation of the alpha-subunit eukaryotic initiation factor-2 (eIF2), and its attendant regulation of gene expression, in the cellular stress response to proteasome inhibition. Phosphorylation of eIF2alpha in mouse embryo fibroblast (MEF) cells subjected to proteasome inhibition leads to a significant reduction in protein synthesis, concomitant with induced expression of the bZIP transcription regulator, ATF4, and its target gene CHOP/GADD153. The primary eIF2alpha kinase activated by exposure of these fibroblast cells to proteasome inhibition is GCN2 (EIF2AK4), which has a central role in the recognition of cytoplasmic stress signals. Endoplasmic reticulum (ER) stress is not effectively induced in MEF cells subjected to proteasome inhibition, with minimal activation of the ER stress sensory proteins, eIF2alpha kinase PEK (PERK/EIF2AK3), IRE1 protein kinase and the transcription regulator ATF6 following up to 6 h of proteasome inhibitor treatment. Loss of eIF2alpha phosphorylation thwarts caspase activation and delays apoptosis. Central to this pro-apoptotic function of eIF2alpha kinases during proteasome inhibition is the transcriptional regulator CHOP, as deletion of CHOP in MEF cells impedes apoptosis. We conclude that eIF2alpha kinases are integral to cellular stress pathways induced by proteasome inhibitors, and may be central to the efficacy of anticancer drugs that target the ubiquitin/proteasome pathway.
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PMID:Phosphorylation of the alpha-subunit of the eukaryotic initiation factor-2 (eIF2alpha) reduces protein synthesis and enhances apoptosis in response to proteasome inhibition. 1568 20

A monomethylated selenium metabolite, called methylseleninic acid (MSA), has recently been shown to cause global thiol redox modification of proteins. These changes represent a form of cellular stress due to protein misfolding or unfolding. An accumulation of aberrantly folded proteins in the endoplasmic reticulum (ER) triggers a defined set of transducers to correct the defects or commit the cells to apoptosis if the rescue effort is exhausted. Treatment of PC-3 human prostate cancer cells with MSA was found to induce a number of signature ER stress markers: (a) the survival/rescue molecules such as phosphorylated protein kinase-like ER-resident kinase (phospho-PERK), phosphorylated eukaryotic initiation factor-2alpha (phospho-eIF2alpha), glucose-regulated protein (GRP)-78, and GRP94; and (b) the apoptotic molecules such as caspase-12, caspase-7, and CAAT/enhancer binding protein homologous protein or growth arrest DNA damage-inducible gene 153 (CHOP/GADD153). Additional evidence suggested that CHOP/GADD153 might be an important transcription factor in apoptosis induction by MSA. In general, a higher concentration of MSA was required to elicit the apoptotic markers compared with the rescue markers. The apoptotic markers increased proportionally with the dose of MSA, whereas the rescue markers failed to keep pace with the increasing challenge from MSA. GRP78 is the rheostat of the ER stress transducers. In GRP78-overexpressing cells, the ability of MSA to up-regulate phospho-PERK, phospho-eIF2alpha, GRP94, caspase-12, caspase-7, and CHOP/GADD153 was significantly muted. A generous supply of GRP78 would allow cells to cope better with ER stress, thereby improving the odds for survival and negating the commitment to apoptotic death. The present study thus provides strong evidence to support an important role of ER stress response in mediating the anticancer effect of selenium.
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PMID:Endoplasmic reticulum stress signal mediators are targets of selenium action. 1620 82

Redox modification of thiol/disulfide interchange in proteins by selenium could lead to protein unfolding. When this occurs in the endoplasmic reticulum (ER), a process known as unfolded protein response (UPR) is orchestrated for survival through activation of PERK-eIF2alpha (PERK: double-stranded RNA-activated protein kinase-like ER kinase; eIF2alpha: eucaryotic initiation factor 2alpha), ATFalpha (ATFalpha: activating transcription factor 6) and inositol requiring 1 (IRE1)-x-box-binding protein 1 (XBP1) signalings. All three UPR transducer pathways were upregulated very rapidly when PC-3 cells were exposed to selenium. These changes were accompanied by increased expression of UPR target genes, including immunoglobulin heavy chain-binding protein/glucose-regulated protein, 78 kDa and CCAAT/enhancer binding protein-homologous protein/growth arrest- and DNA damage-inducible gene (CHOP/GADD153). Induction of BiP/GRP78, an ER-resident chaperone, is part of the damage control mechanism, while CHOP/GADD153 is a transcription factor associated with growth arrest and apoptosis in the event of prolonged ER stress. Knocking down BiP/GRP78 induction by small interference RNA produced a differential response of the three transducers to selenium, suggesting that the signaling intensity of each transducer could be fine-tuned depending on BiP/GRP78 availability. In the presence of selenium, CHOP/GADD153 expression was raised even higher by BiP/GRP78 knockdown. Under this condition, the selenium effect on wild-type p53-activated fragment p21 (p21(WAF)), cyclin-dependent kinase (CDK)1 and CDK2 was also magnified in a manner consistent with enhanced cell growth arrest. Additional experiments with CHOP/GADD153 siRNA knockdown strongly suggested that CHOP/GADD153 may play a positive role in upregulating the expression of p21(WAF) in a p53-independent manner (PC-3 cells are p53 null). Collectively, the above findings support the idea that UPR could be an important mechanism in mediating the anticancer activity of selenium.
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PMID:Enhanced selenium effect on growth arrest by BiP/GRP78 knockdown in p53-null human prostate cancer cells. 1620 45

In response to environmental stresses, a family of protein kinases phosphorylate eIF2 (eukaryotic initiation factor 2) to alleviate cellular injury or alternatively induce apoptosis. Phosphorylation of eIF2 reduces global translation, allowing cells to conserve resources and to initiate a reconfiguration of gene expression to effectively manage stress conditions. Accompanying this general protein synthesis control, eIF2 phosphorylation induces translation of specific mRNAs, such as that encoding the bZIP (basic leucine zipper) transcriptional regulator ATF4 (activating transcription factor 4). ATF4 also enhances the expression of additional transcription factors, ATF3 and CHOP (CCAAT/enhancer-binding protein homologous protein)/GADD153 (growth arrest and DNA-damage-inducible protein), that assist in the regulation of genes involved in metabolism, the redox status of the cells and apoptosis. Reduced translation by eIF2 phosphorylation can also lead to activation of stress-related transcription factors, such as NF-kappaB (nuclear factor kappaB), by lowering the steady-state levels of short-lived regulatory proteins such as IkappaB (inhibitor of NF-kappaB). While many of the genes induced by eIF2 phosphorylation are shared between different environmental stresses, eIF2 kinases function in conjunction with other stress-response pathways, such as those regulated by mitogen-activated protein kinases, to elicit gene expression programmes that are tailored for the specific stress condition. Loss of eIF2 kinase pathways can have important health consequences. Mice devoid of the eIF2 kinase GCN2 [general control non-derepressible-2 or EIF2AK4 (eIF2alpha kinase 4)] show sensitivity to nutritional deficiencies and aberrant eating behaviours, and deletion of PEK [pancreatic eIF2alpha kinase or PERK (RNA-dependent protein kinase-like endoplasmic reticulum kinase) or EIF2AK3] leads to neonatal insulin-dependent diabetes, epiphyseal dysplasia and hepatic and renal complications.
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PMID:Coping with stress: eIF2 kinases and translational control. 1624 68


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