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)

Overexpression of heat shock protein 70 kDa alters the susceptibility of tumor cells to chemotherapeutic agents. We conducted experiments to study the regulation of expression of heat shock proteins (HSPs) in heat shock-treated T47-D cells, a human breast cancer cell line that expresses estrogen receptors. Cells exposed to heat shock at 44 degreesC displayed increased expression of heat shock protein 72 kDa (HSP-72), glucose-regulated protein 78 kDa (GRP-78), and GRP-94 in a time-dependent manner, as shown by [35S]methionine incorporation and Western blotting experiments. The maximal rate of synthesis occurred between 2 and 4 h after heat shock. Removal of external Ca2+ inhibited the synthesis of the heat shock-induced GRP-78 but not of HSP-72 and GRP-94, whereas treatment of cells with BAPTA (a Ca2+ chelator) inhibited HSP-72 and GRP-78. Treatment with H89 (a protein kinase A inhibitor) blocked the heat shock-induced GRP-78 synthesis, whereas GF-109203X (a protein kinase C inhibitor) attenuated the heat shock-induced HSP-72 synthesis and completely blocked synthesis of GRP-78 but not of GRP-94. These results indicate that protein kinase C is involved in regulation of the heat shock-induced synthesis of HSP-72, whereas PKA and PKC are involved in the regulation of GRP-78 synthesis. Cells overexpressing HSP-72 and GRPs after heat shock displayed resistance against lethal temperature (47 degreesC for 50 min) -induced death, which was diminished after removal of external Ca2+ and treatment with GF-109203X. Heat shock increased intracellular free Ca2+ concentration ([Ca2+]i) in a temperature- and heating duration-dependent fashion, and the increase was inhibited in the absence of external [Ca2+]i and significantly reduced by pretreatment with H89 and GF-109203X. The results suggest that different pathways are involved in the induction of synthesis of HSP-72, GRP-78, and GRP-94 by heat shock. It is highly likely that only HSP-72 and GRP-78 are involved in the process of cytoprotection from the thermal injury.
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PMID:Cytoprotection and regulation of heat shock proteins induced by heat shock in human breast cancer T47-D cells: role of [Ca2+]i and protein kinases. 980 66

In cultured renal cells, hypertonicity activates multiple mitogen-activated protein kinases (MAPKs) and enhances the expression of heat shock proteins (HSPs). In rats, 24 h water restriction increased mean urinary osmolality (Uosm) from 2, 179+/-153 mOsm/kg to 2,944+/-294 mOsm/kg (P < 0.001) and was associated with significant (P < 0.05) increases in the papillary activity of c-Jun NH2-terminal protein kinase (JNK) by 22%, extracellular signal-regulated protein kinase (ERK) by 49%, and p38 MAPK by 15%. Conversely, 24 h of water-loading (Uosm 473+/-33 mOsm/kg) caused suppression of JNK activity by 43% (P < 0.001), ERK by 39% (P < 0.05), and p38 MAPK by 26% (P < 0.05). No such modulation was observed in the isotonic cortex. c-Jun phosphorylation was decreased in papilla from water-loaded rats by 45% versus controls. Expression of Hsp 110, inducible Hsp 70, and Hsp 25 was greater in the hyperosmotic papilla than the isosmotic cortex but was not affected by the animal's hydration state. In cultured inner medullary collecting duct cells, HSP expression was maximal at 500 mOsm/kg, while activation of JNK continued to increase. We conclude that under basal conditions of hydration, these HSPs are maximally expressed in the hypertonic inner medulla, while the activation of all three members of the MAPK family approaches but is not maximal.
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PMID:In vivo regulation of MAP kinases in Ratus norvegicus renal papilla by water loading and restriction. 981 74

Cyclic nucleotide-dependent vasorelaxation is associated with increases in the phosphorylation of a small heat shock-related protein, HSP20. We hypothesized that phosphorylation of HSP20 in vascular smooth muscles is associated with alterations in the macromolecular associations of HSP20. Treatment of bovine carotid artery smooth muscles with the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, and the adenylate cyclase activator, forskolin, led to increases in the phosphorylation of HSP20 and dissociation of macromolecular aggregates of HSP20. However, 3-isobutyl-1-methylxanthine and forskolin treatment of a muscle that is uniquely refractory to cyclic nucleotide-dependent vasorelaxation, human umbilical artery smooth muscle, did not result in increases in the phosphorylation of HSP20 or to dissociation of macromolecular aggregates. HSP20 can be phosphorylated in vitro by the catalytic subunit of cAMP-dependent protein kinase (PKA) in both carotid and umbilical arteries and this phosphorylation of HSP20 is associated with dissociation of macromolecular aggregates of HSP20. Activation of cyclic nucleotide-dependent signaling pathways does not lead to changes in the macromolecular associations of another small heat shock protein, HSP27. Interestingly, the myosin light chains (MLC20) are in similar fractions as the HSP20, and phosphorylation of HSP20 is associated with changes in the macromolecular associations of MLC20. These data suggest that increases in the phosphorylation of HSP20 are associated with changes in the macromolecular associations of HSP20. HSP20 may regulate vasorelaxation through a direct interaction with specific contractile regulatory proteins.
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PMID:Phosphorylation of the small heat shock-related protein, HSP20, in vascular smooth muscles is associated with changes in the macromolecular associations of HSP20. 1003 21

The heat shock transcription factor Hsf1p and the stress-responsive transcription factors Msn2p and Msn4p are activated by heat shock in the yeast Saccharomyces cerevisiae. Their respective contributions to heat shock protein induction have been analysed by comparison of mutants and wild-type strains using [35S]-methionine labelling and two-dimensional gel electrophoresis. Among 52 proteins induced by a shift from 25 degrees C to 38 degrees C, half of them were found to be dependent upon Msn2p and/or Msn4p (including mostly antioxidants and enzymes involved in carbon metabolism), while the other half (including mostly chaperones and associated proteins) were dependent upon Hsf1p. The two sets of proteins overlapped only slightly. Three proteins were induced independently of these transcription factors, suggesting the involvement of other transcription factor(s). The Ras/cAMP/PKA signalling pathway cAMP had a negative effect on the induction of the Msn2p/Msn4p regulon, but did not affect the Hsf1p regulon. Thus, the two types of transcription factor are regulated differently and control two sets of functionally distinct proteins, suggesting two different physiological roles in the heat shock cellular response.
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PMID:The heat shock response in yeast: differential regulations and contributions of the Msn2p/Msn4p and Hsf1p regulons. 1041 44

Human skin is repeatedly exposed to mechanical stretching in vivo, but in an ordinary culture of skin cells this prominent feature has been neglected. In order to study whether mechanical stretching plays a role for human melanocytes, we have established a culture technique to mimic this physical stretching: primary cultures of human melanocytes were plated on silicon supports, which undergo a stretching of about 10% of the initial length. After application of repeated stretching and relaxation for 4 days, cell count was significantly (about 40%) enhanced. In addition, we found approximately 2-fold increase in heat shock protein (HSP) 90, both at the protein and mRNA level. HSP 90 is known to bind to Raf-1 and, therefore, may contribute to the Raf-1-MEK (mitogen-activated protein-kinase kinase)-MAPK (mitogen-activated protein-kinase) signaling pathway. Disruption of the Raf-1-HSP 90 multimolecular complex by geldanamycin lead to a considerable decrease in melanocyte cell count. However, geldanamycin did not reverse the stretch-induced growth stimulation. Therefore, the stretch-mediated up-regulation of HSP 90 expression in melanocytes appears to be independent of stretch-mediated growth stimulation. These findings have strong implications for the in vitro cultivation of melanocytes for transplantation purposes.
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PMID:Cyclic stretch up-regulates proliferation and heat shock protein 90 expression in human melanocytes. 1045 92

We investigated the effects of a protein kinase (PK) inhibitor, H-7 (1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride), on the regulation of heat shock protein (hsp)72 gene expression in a human glioblastoma cell line (A-172) using a gel mobility-shift assay and Western blot analysis. Heat shock transcription factor 1 (HSF1) was phosphorylated immediately after heat treatment (44 degrees C, 30 min) and the phosphorylation of HSF1 was suppressed by H-7. The increase in DNA binding ability of HSFI to heat shock element (HSE) by heat shock was significantly suppressed by the addition of H-7 in a dose-dependent manner. Similarly, the accumulation of hsp72 by heat shock was suppressed by the addition of H-7 in a dose-dependent manner. Since H-7 is known to be a potent inhibitor of some PKs, especially calcium-dependent PK (PKC), cyclicAMP-dependent PK (PKA) and cyclicGMP-dependent PK (PKG), it is possible that the activation of HSF1 by phosphorylation and subsequent hsp72 gene expression are dependent on some of those PKs. The nature of H-7 as a non-specific inhibitor for PKs is discussed in relation to its availability for regulation of heat sensitivity of cells depending on cellular level of hsp72.
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PMID:The protein kinase inhibitor, H-7, suppresses heat induced activation of heat shock transcription factor 1. 1048 32

Basal and stress-induced synthesis of the components of the highly conserved heat shock protein Hsp90 chaperone complex require the heat shock transcription factor (HSF); Saccharomyces cerevisiae cells expressing the HSF allele HSF(1-583) reversibly arrest growth at 37 degrees C in the G(2)/M phase of the cell cycle due to diminished expression of these components. A suppressor mutant capable of restoring high-temperature growth to HSF(1-583) cells was identified, harboring a disruption of the SCH9 protein kinase gene, homologous to the protein kinase A and protein kinase B/Akt families of mammalian growth control kinases. Loss of Sch9 in HSF(1-583) cells derepresses Hsp90 signal transduction functions as demonstrated by restoration of transcriptional activity by the mammalian glucocorticoid receptor and the heme-dependent transcription factor Hap1, and by enhanced pheromone-dependent signaling through the Ste11 mitogen-activated protein kinase (MAPK). Moreover, Sch9-deficient cells with normal levels of Hsp90 chaperone complex components display hyperactivation of the pheromone response MAPK pathway in the absence of pheromone. These results demonstrate that the evolutionarily conserved function of the Hsp90 chaperone complex as a signal transduction facilitator is modulated by a growth regulatory kinase.
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PMID:The Sch9 protein kinase regulates Hsp90 chaperone complex signal transduction activity in vivo. 1054 7

The 90-kDa heat shock protein (Hsp90) is the most abundant molecular chaperone of eukaryotic cells. Its chaperone function in folding nascent proteins seems to be restricted to a subset of proteins including major components of signal transduction pathways (eg, nuclear hormone receptors, transcription factors, and protein kinases). Improper function of these proteins can be induced by selective disruption of their complexes with Hsp90 using the benzoquinonoid ansamycin geldanamycin. In this study, we demonstrate that geldanamycin treatment blocks interleukin (IL)-2 secretion, IL-2 receptor expression, and proliferation of stimulated T-lymphocytes. Moreover, geldanamycin decreases the amount and phosphorylation of Lck and Raf-1 kinases and prevents activation of the extracellular signal regulated kinase (ERK)-2 kinase. Geldanamycin also disrupts the T-cell receptor-mediated activation of nuclear factor of activated T-cells (NF-AT). Treatment with geldanamycin, however, does not affect the activation of lysophosphatide acyltransferase, which is a plasma membrane enzyme coupled to the T-cell receptor after T-cell stimulation. Through demonstrating the selective inhibition of kinase-related T-lymphocyte responses by geldanamycin, our results emphasize the substantial role of Hsp90-kinase complexes in T-cell activation.
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PMID:The Hsp90-specific inhibitor geldanamycin selectively disrupts kinase-mediated signaling events of T-lymphocyte activation. 1070 40

Substances that increase intracellular calcium concentration ([Ca(2+)](i)), such as serotonin, are known to induce vascular smooth muscle (VSM) contraction. However, increases in [Ca(2+)](i) also activate Ca(2+)/calmodulin-dependent nitric oxide synthases (NOS), which leads to increases in cGMP and activation of cGMP-dependent protein kinase (PKG). One recently identified substrate protein of PKG is the small heat shock protein, HSP20. The purpose of this study was to determine if serotonin activates a Ca(2+)-dependent NOS in VSM. Strips of bovine carotid arterial smooth muscle denuded of endothelium were stimulated with serotonin in the presence and absence of the nonspecific NOS inhibitor N-monomethyl-L-arginine (L-NMMA). Activation of NOS was determined by increases in cGMP and in the phosphorylation of HSP20. Immunohistochemical and Western blotting techniques were performed to identify specific NOS isoforms in bovine carotid arterial smooth muscle preparations. Serotonin stimulation led to significant increases in cGMP and in the phosphorylation of HSP20, which were inhibited by pretreatment with L-NMMA. Antibodies against NOS 1 stained the media of bovine carotid and human renal arteries, whereas antibodies against NOS 3 stained only the endothelium. Additionally, the conversion of radiolabeled L-arginine to L-citrulline NOS activity demonstrated a consistent amount of activity present in the endothelium-denuded smooth muscle preparations that was reduced by 99% with an NOS 1 specific inhibitor. Finally, an NOS 1 specific inhibitor, 7-nitroindazole, augmented contractions induced by high extracellular KCl. This study demonstrates that NOS 1 is present in VSM and may effect physiological contractile responses.
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PMID:Functional expression of NOS 1 in vascular smooth muscle. 1071 Mar 69

It has been shown that expression of HSPs can negatively regulate the effectiveness of cytotoxic drugs. In this study, we conducted experiments to study the regulation of expression of heat shock proteins (HSPs) in human breast cancer MDA-MB-231 cells. Using [35S]methionine incorporation and Western immunoblots, we established that heat shock increased production of HSP-72 and -90. Cells exposed to 44 degrees C for 20 min displayed increased expression of HSP-72 and -90, that reached a maximum 3-7 h later and returned to baseline levels within 24 h. The synthesis of both HSP-72 and -90 was attenuated when cells were exposed to heat shock in medium devoid of Ca2+ or pretreated with the calcium chelator BAPTA for 30 min prior to heat shock. Similarly, synthesis of HSP-72 and -90 was inhibited when cells were treated with the protein kinase A inhibitor, H89. These data indicate that Ca2+ and PKA are involved in the regulation of HSP-72 and -90 protein synthesis. Levels of HSP-72 mRNA in cells exposed to heat shock increased, suggesting that the heat-induced increase in HSP-72 occurs at the transcriptional level. Also, heat shock caused phosphorylation and translocation from the cytosol to the nucleus of heat shock factor 1 (HSF 1), a transcription factor for heat shock protein synthesis. Removal of external Ca2+ or treatment with a PKA inhibitor prevented the phosphorylation and the translocation of HSF 1. Cells overexpressing HSP-72 and -90 induced by exposure to a sublethal temperature displayed cytoprotection from thermal injury. Removal of external Ca2+ and treatment with BAPTA or H89 prior to exposure to sublethal heat shock that reduced the amount of HSP-72 and -90 production still protected cells from subsequent thermal injury. The intracellular free calcium concentration ([Ca2+]i) in resting fura-2-loaded MDA-MB-231 cells was 175+/- nM. Heat shock increased [Ca2+]i in a time-and temperature-dependent manner. Exposure of cells to 44 degrees C for 20 min increased [Ca2+]i by 234+/-13%, which subsequently returned to baseline levels within 30 min. Removal of external Ca2+ eliminated the increase, indicating that the increase in [Ca2+]i was due to Ca2+ influx. Pretreatment of the cells with H89 but not GF-109203X for 30 min led to an attenuation of the increase in [Ca2+]i by a subsequent heat shock. The results suggest that HSP-72 and -90 are regulated by [Ca2+]i and PKA activity in MDA-MB-231 cells. Kiang JG, Gist ID, Tsokos GC: Regulation of Heat Shock Protein 72 kDa and 90 kDa in Human Breast Cancer MDA-MB-231 Cells.
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PMID:Regulation of heat shock protein 72 kDa and 90 kDa in human breast cancer MDA-MB-231 cells. 1071 36


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