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)

An underinvestigated aspect of the mitogenic and cell regulatory actions of vanadium is the regulation of gene expression. Among the fifteen cellular genes studied in cultured mouse C127 cells, vanadium (as 10 microM sodium vanadate) increased levels of mRNA of the actin and c-Ha-ras to four times control values. These increases represented de novo synthesis of mRNA, since they were inhibited by actinomycin D. Vanadate did not increase mRNA corresponding to c-src, c-mos, c-myc, p53, HSP70, pODC or RB genes, and expression of c-erb A, c-erb B, c-sis and c-fes genes was undetectable whether vanadium was present or not. Expression of a third gene affected by vanadium, c-jun, was augmented by addition of a reductant or oxidant together with the vanadate. Addition of NADH (marginally effective on its own) or H2O2 (effective alone) dramatically enhanced the effect of vanadate on c-jun gene expression. Catalase inhibited the effect of NADH partly. The vanadate-stimulated expression of actin and c-Ha-ras mRNA were unaffected by oxidants, reductants, metal chelators, or anti-oxidant enzymes. Evidently vanadate acts by two separate mechanisms on these two categories of genes. The alternate hypothesis that the actions of vanadate on actin and c-Ha-ras were mediated by a protein kinase cascade was inconsistent with the following observations. Neither insulin nor epidermal growth factor increased mRNA levels of c-Ha-ras or actin gene. Neither genistein (a tyrosine kinase inhibitor) nor pretreatment with 12-O-tetradecanoylphorbol-13-acetate blocked the actions of vanadate on these genes. Clearly the biological actions of vanadium depend in part on altered expression of genes. Since two of the genes are proto-oncogenes, this mechanism is potentially relevant to the mitogenic responses of cells to vanadium.
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PMID:Vanadate-induced gene expression in mouse C127 cells: roles of oxygen derived active species. 143 69

HSP70 genes exhibit complex regulation in response to stress and a variety of cellular and developmental events. The SSA3 HSP70 gene of Saccharomyces cerevisiae is activated at the transcriptional level under conditions of nutrient limitation. Analysis of deletions revealed that cis-acting DNA sequences present immediately upstream and downstream of the previously identified heat shock elements (UASHS) mediate this regulation. A 35 bp region of SSA3, distinct from UASHS, contains sequences capable of activating a heterologous promoter following the diauxic shift and in the stationary phase of the yeast life cycle; this region has been designated an upstream activating sequence, UASPDS. Expression driven by UASPDS is regulated by the RAS/cAMP pathway. Reduced cAMP dependent protein kinase activity results in UASPDS dependent activation of the SSA3 promoter while constitutive cAMP dependent protein kinase activity prevents UASPDS mediated transcription, even under growth conditions that would normally result in full activation. Although the heat shock element alone exhibits no UAS activity under conditions in which UASPDS promotes transcription, UASHS interacts positively with UASPDS to mediate high levels of SSA3 transcription in response to nutrient limitation and lowered intracellular cAMP concentration. This interaction is independent of the precise spacing and relative orientation of the two elements.
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PMID:Regulation of a yeast HSP70 gene by a cAMP responsive transcriptional control element. 169 49

Protooncogene fos is rapidly and transiently induced by nerve growth factor (NGF) in rat pheochromocytoma PC12 cells. Two adjacent promoter elements have been identified to mediate the NGF response. One element colocalizes with the serum response element (SRE) centered at position -308, previously shown to confer inducibility by serum, phorbol 12-myristate 13-acetate, and epidermal growth factor, whereas the other element, termed SRE-2, maps approximately 20 base pairs downstream of the SRE and contains several sequence repeats. This element also confers serum responsiveness. Gel mobility shift assays have demonstrated that there are specific nucleoprotein complexes associated with each element and that these exist in the cell prior to NGF induction. The NGF response is independent of the cAMP-regulatory element(s) and does not require cAMP-dependent protein kinase II, as induction by NGF is retained in the mutant PC12 cell line A126-1B2. Finally, the human heat shock HSP70 promoter is also transcriptionally activated by NGF and appears to bind the same nuclear complex as the SRE-2 element of the c-fos promoter.
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PMID:Two adjacent promoter elements mediate nerve growth factor activation of the c-fos gene and bind distinct nuclear complexes. 284 7

Regulation of translation during heat shock of Drosophila and mammalian cells is reviewed. Protein synthesis is severely inhibited by elevated temperatures but synthesis of heat shock proteins (HSPs) is resistant to this inhibition. The primary site of regulation is polypeptide chain initiation. The activities of two initiation factors, eIF-2 and eIF-4F, are modulated during heat shock. A protein kinase which modulates eIF-2 activity appears to be associated with heat shock proteins (HSPs). Evidence is emerging that HSP70 acts as a heat sensor by detecting the presence of accumulating denatured proteins. In the rabbit reticulocyte lysate denatured proteins bind HSP70 releasing an eIF-2 kinase to shut down protein synthesis. It appears highly likely that a similar mechanism is acting in heat shocked cells. Cell-free protein synthesizing systems prepared from heat shocked cells are deficient in eIF-4F. Modulation of eIF-4F can explain in part the apparent preferential translation of HSP mRNAs.
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PMID:Translational control during heat shock. 789 24

The possible involvement of PKC in the regulation of heat shock genes expression was investigated with three isoquinolinesulfonamide derivatives (H-7, H-8, and HA1004) in DUT-145, MCF-7, and MCF-7/ADR cells. The drug was added 1 hr before and during heating at 41 degrees C. Northern blots show that the levels of HSP70 and HSP28 mRNA increased rapidly and reached maximal values within 4-8 hr and 8-12 hr, respectively. H-7 and H-8 which are potent PKC inhibitors selectively suppressed the accumulation of HSP70 mRNA as well as the synthesis of HSP70. In contrast, HA1004 which is a potent PKA inhibitor but a weak PKC inhibitor did not affect HSP70 gene expression. These results suggest that PKC rather than PKA plays an important role in the regulation of heat shock gene expression.
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PMID:Effect of isoquinolinesulfonamides on heat shock gene expression during heating at 41 degrees C in human carcinoma cell lines. 813 14

A Z-DNA binding protein has been isolated and characterized by biochemical means from Drosophila melanogaster tissue culture cells and embryos. This protein shares the following properties with the known, cloned Drosophila topoisomerase II: (1) expression of an ATP-dependent relaxation activity on supercoiled DNA; (2) a monomer mass of 165 kDa in SDS denaturing gels; (3) a sedimentation coefficient, S20,w, of approximately 10 S for the active enzyme; (4) cross-reactivity for the respective monoclonal and polyclonal antibodies; (5) generation of covalent enzyme-DNA intermediates at preferred cutting sites in the Drosophila HSP70 intergenic spacer region; (6) inhibition of DNA relaxation activity by antitumor drugs, e.g., the etoposide VM26, and by monospecific antibodies raised against the protein; and (7) in vitro phosphorylation by a casein kinase activity. However, we have identified new properties for our topoisomerase II preparation not previously reported for the conventionally isolated enzyme: (1) The enzyme binds to Z-DNA with an affinity 2 orders of magnitude greater than that for B-DNA. (2) The binding to Z-DNA is increased 5-10-fold by GTP or GTP-gamma-S. (3) GTP and GTP-gamma-S inhibit the catalytic activity of topoisomerase II through a proposed allosteric mechanism. (4) Z-DNA inhibits the relaxation of closed circular supercoiled DNA. (5) The preparation consists of a single polypeptide chain of 165 kDa on denaturing SDS gels with no evidence of proteolytic degradation. We postulate that the Z-DNA binding activity of undegraded topoisomerase II may be important in targeting the enzyme both to structural motifs required for chromatin organization and to sites of local supercoiling. Some of these features arise during processes such as replication and gene expression and may be more frequent during embryogenesis and early development.
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PMID:Z-DNA binding and inhibition by GTP of Drosophila topoisomerase II. 838 19

The ume3-1 allele was identified as a mutation that allowed the aberrant expression of several meiotic genes (e.g. SPO11, SPO13) during mitotic cell division in Saccharomyces cerevisiae. Here we report that UME3 is also required for the full repression of the HSP70 family member SSA1. UME3 encodes a non-essential C-type cyclin (Ume3p) whose levels do not vary through the mitotic cell cycle. However, Ume3p is destroyed during meiosis or when cultures are subjected to heat shock. Ume3p mutants resistant to degradation resulted in a 2-fold reduction in SPO13 mRNA levels during meiosis, indicating that the down-regulation of this cyclin is important for normal meiotic gene expression. Mutational analysis identified two regions (PEST-rich and RXXL) that mediate Ume3p degradation. A third destruction signal lies within the highly conserved cyclin box, a region that mediates cyclin-cyclin-dependent kinase (Cdk) interactions. However, the Cdk activated by Ume3p (Ume5p) is not required for the rapid destruction of this cyclin. Finally, Ume3p destruction was not affected in mutants defective for ubiquitin-dependent proteolysis. These results support a model in which Ume3p, when exposed to heat shock or sporulation conditions, is targeted for destruction to allow the expression of genes necessary for the cell to respond correctly to these environmental cues.
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PMID:Stress and developmental regulation of the yeast C-type cyclin Ume3p (Srb11p/Ssn8p). 930 11

This laboratory reported previously that overexpressed heat shock protein 70 kDa (HSP-70) inhibited the activation of its transcriptional factor, HSF1. We had conducted experiments to understand the mechanisms whereby HSP-70 down-regulated the activation of HSF1. Genetically overexpressed HSP-70 had no effects on the HSF1 level in cytosol, but significantly inhibited phosphorylation of HSF1 in the nucleus. Transfection of cells with HSF1 cDNA resulted in increases in the unphosphorylated, but not phosphorylated, HSF1 levels in both the cytosol and nucleus. Because serine phosphorylation of various proteins was reduced in HSP-70 cDNA-transfected cells, we measured the activity of enzymes involved in serine phosphorylation. Overexpressed HSP-70 significantly inhibited the enzymatic activities of protein kinase A (PKA by 73 and 62% in the cytosol and membrane-bound fraction, respectively) and protein kinase C (PKC by 61% in membrane-bound fraction), whereas it activated that of protein phosphatase (PP by 33 and 86% in the cytosol and the membrane-bound fraction, respectively). Forskolin (a PKA stimulator), PMA (a PKC stimulator), and okadaic acid (an inhibitor of PP) were used to investigate whether HSP-70-induced changes in PKA, PKC, and PP were responsible for the HSF1 dephosphorylation. Forskolin did not change nuclear HSF1 phosphorylation, suggesting that decreases in PKA activity in HSP-70 overexpressing cells is not associated with HSF1 phosphorylation. PMA and okadaic acid induced an increase in HSF1 phosphorylation in both vector- and HSP-70 cDNA-transfected cells, although levels of phosphorylated HSF1 in HSP-70 cDNA-transfected cells were lower than those in vector-transfected cells. The PMA-induced increase in HSF1 phosphorylation in HSP-70 cDNA-transfected cells was blocked by pretreatment with staurosporine, a PKC inhibitor. These results suggest that overexpression of HSP-70 inhibits phosphorylation of HSF1 at serine residues by activating PP and inhibiting PKC activity.
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PMID:Overexpression of HSP-70 inhibits the phosphorylation of HSF1 by activating protein phosphatase and inhibiting protein kinase C activity. 953 17

Rats were subjected to transient cerebral ischemia by four-vessel occlusion of 30 min duration, followed by 2, 4, 8 or 24 h of recovery. Total RNA was isolated from the cerebral cortex and hippocampus, and reverse transcribed into cDNA. Hsp40 mRNA levels of samples were evaluated by quantitative PCR. Transient cerebral ischemia caused a marked increase in hsp40 mRNA levels to about 250% and 500% of control in the cortex and hippocampus respectively. Since hsp40 exerts a critical regulatory function in the HSC70/HSP70 ATPase cycle, an ischemia-induced rise of hsp40 mRNA levels could mark the onset of the recovery process after transient ischemia. On the other hand, the inhibitory action of hsp40 on P58 (a protein that activates protein synthesis by blocking the interferon-induced double-stranded RNA-activated protein kinase PKR) implies that the rise in hsp40 expression may equally well contribute to the post-ischemic suppression of protein synthesis.
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PMID:Effects of transient cerebral ischemia on hsp40 mRNA levels in rat brain. 958 51

The HSP70 heat-shock proteins are molecular chaperones that assist other proteins in folding, transport, and assembly into complexes. The genes for these proteins are either constitutively expressed (Hsc70, Grp78), or their expression is induced by heat shock and other stresses (Hsp70-1, Hsp70-3). Two additional genes encode proteins that are developmentally regulated and expressed specifically in spermatogenic cells (Hsp70-2, Hsc70t). The HSP70-2 protein is synthesized during the meiotic phase of spermatogenesis and is abundant in pachytene spermatocytes. Studies in transgenic mice indicated that the region between nucleotides -640 and +1 contains promoter sequences necessary for expression of Hsp70-2 in spermatocytes. Because of the pattern of gene expression, it was hypothesized that HSP70-2 is a chaperone necessary for completion of meiosis in spermatogenic cells. The gene knockout approach was used to test this hypothesis, and it was found that male mice homozygous for the mutation were infertile, whereas homozygous females were fertile. Spermatogenesis was disrupted, with the nuclei of late pachytene spermatocytes often appearing fragmented and spermatids being absent. Disruption of spermatogenesis occurred at the G2-M phase transition in prophase of meiosis I, and all pachytene spermatocytes underwent apoptosis. It was demonstrated that HSP70-2 is a chaperone for Cdc2, with their association allowing Cdc2 to acquire the necessary conformation to form a heterodimer with cyclin B1, leading to changes in Cdc2 phosphorylation and the development of kinase activity necessary for the G2-M phase transition. This appears to be the first demonstration that interaction between an HSP70 protein and a cyclin-dependent kinase is necessary for progression of the cell cycle.
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PMID:HSP70-2 heat-shock protein of mouse spermatogenic cells. 972 83


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