Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parathyroid hormone (PTH) activates both adenylate cyclase and phospholipase C in target cells, and cloned PTH/PTH-related protein (PTHrP) receptor can mediate both responses when expressed in host cells such as LLC-PK1 renal epithelial cells. Because calcitonin (CT) is known to augment 70-kDa heat shock protein (HSP70) mRNA by an adenosine 3',5'-cyclic monophosphate (cAMP)-independent mechanism in LLC-PK1 cells, we examined regulation of HSP70 transcription by PTH in these cells. Like CT, human PTH-(1-34) [hPTH-(1-34); 10(-10) to 10(-7) M)] increased porcine HSP70 mRNA and human HSP70 promoter-chloramphenicol acetyltransferase (CAT) expression within 4 h in LLC-PK1 cells that stably express > or = 100,000 PTH/PTHrP receptors per cell. The effect of PTH on HSP70 mRNA was not mimicked by cAMP analogues, forskolin, phorbol esters, Ca2+ ionophores, or alpha-thrombin; was insensitive to pertussis toxin; and was not due to increased mRNA stability. The upregulation of HSP70 gene transcription by hPTH (and CT) was clearly observed even after deletion of the functional heat shock consensus element in the promoter region of the human HSP70/CAT reporter. Upregulation of HSP70 transcription via endogenous PTH receptors also was observed in the osteoblastic cell lines SaOS-2 and ROS 17/2.8. Regulation of HSP70 gene transcription by PTH may be a common cellular response to the hormone, which, in some cells, may not be mediated by activation of adenylate cyclase or protein kinase C.
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PMID:Regulation of HSP70 by PTH: a model of gene regulation not mediated by changes in cAMP levels. 876 37

Activation of the latent DNA binding function of human p53 protein by the bacterial Hsp70, DnaK, represents a unique reaction in which a heat shock protein can interact with a native protein to affect its function. We have localized a likely DnaK interaction site on native human p53 tetramers to a motif flanking the COOH-terminal casein kinase II and protein kinase C phosphorylation sites. Murine p53 is less efficiently activated by DnaK, which has permitted a search for factors that might cooperate in p53 activation by DnaK. We show that optimal activation by DnaK may be dependent upon the phosphorylation state of murine p53, in particular, modification of p53 at the cdc2 phosphorylation site by point mutation decreases the extent of activation by DnaK. Additionally, the monoclonal antibody PAb241, binding in the vicinity of the cdc2 phosphorylation site, is able to activate the specific DNA binding function of p53. This has led us to propose a second regulatory motif flanking the tetramerization domain of p53 that cooperates with factors binding at the negative regulatory domain in the extreme COOH terminus.
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PMID:Modification of two distinct COOH-terminal domains is required for murine p53 activation by bacterial Hsp70. 894 78

Drug resistance is a major obstacle to successful chemotherapy for cancer. When it occurs, resistance to a wide range of agents is noted. Factors that rule this resistance can be defined as pharmacologic and cellular. Pharmacologic factors are those that prevent an adequate degree of tumor cell exposure and include considerations of dose and schedule of drugs. Cellular factors are those that imply the tumor cell itself and it is probable that multiple mechanisms co-exists: 1) the drug transport across the tumor cell membrane and the duration of the drug exposure, 2) the drug metabolism (activation, inactivation), 3) the cellular targets and the DNA repair processes. The pleiotropic multidrug resistance (mdr, mrp, lrp), alterations of a target enzyme (topoisomerase II, protein kinase C, glutathione S transferase, O6 alkylguanine-DNA alkyltransferase) and the protein modifications (heat shock protein, metallothioneins) are the principal mechanisms involved. Several methods have been established for the determination of the presence of these drug resistance mechanisms but variations in the results are observed with the different methods used. Therefore, the value and the relative importance of these mechanisms in human tumor resistance is not yet established. In the mean-time, strategies to prevent and to overcome this resistance are developed.
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PMID:[Resistance to antineoplastic treatments: mechanisms, clinical value]. 895 96

Heat shock factor-1 (HSF1) is a transcriptional factor that binds to heat shock elements located on the promoter region of heat shock protein genes. The purpose of this study was to further investigate the regulation of the expression of the heat shock protein-70 (HSP-70) gene. The HSF1 gene was inserted into pCDNA3 plasmid and then transfected into human epidermoid A431 cells using the CaOP3 method. Control cells were transfected with vector alone. Expression of HSP-70, HSF1, and HSF2 genes and protein were determined. We found a significant increase in the expression of the HSF1 gene, but not HSP-70 and HSF2 genes, in the HSF1 gene-transfected cells. The amount of HSF1-heat shock element complex was significantly increased in both the nucleus and cytosol in HSF1 gene-transfected cells, indicating increased synthesis of HSF1. The amount of HSP-72 in these cells did not change. Therefore, overexpression of HSF1 protein failed to initiate transcription of the HSP-70 gene. Subsequently, we treated the cells with 1 microM PMA (a protein kinase C stimulator), and HSP-70 mRNA and protein were measured at 1 or 4 h of the treatment, respectively. The levels of both HSP-70 mRNA and HSP-72 protein were significantly increased in nontransfected and transfected cells; the levels of HSP-72 in HSF1 gene-transfected cells were greater than that found in the vector-transfected cells. The PMA-induced increase in HSP-72 protein peaked 8 h after treatment with PMA and returned to baseline levels at 72 h. This increase was blocked by a PKC inhibitor, staurosporine. After treatment with PMA, HSF1 translocated quickly from cytosol to nucleus. The results suggest that phosphorylation of newly synthesized HSF1 and possibly of other factors are necessary for the induction of HSP-72. Activation of PKC can cause phosphorylation of HSF1, which leads to an enhanced but transient increase in HSP-70 production.
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PMID:Heat shock factor-1 protein in heat shock factor-1 gene-transfected human epidermoid A431 cells requires phosphorylation before inducing heat shock protein-70 production. 901 67

The Ah receptor binds aryl hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with high affinity. After binding aryl hydrocarbons, the receptor releases the 90-kDa heat shock protein and forms a dimer with the Arnt protein capable of binding at xenobiotic-responsive elements (XREs) and stimulating the transcription of genes involved in the metabolism of aryl hydrocarbons. The activity of the Ah receptor/ Arnt dimer can be decreased by treatments causing the down-regulation of protein kinase C and decreasing the nuclear accumulation of the receptor. Incubation with acid phosphatase or with alkaline phosphatase has been reported to block XRE binding. Thus the literature suggests that phosphorylation regulates Ah receptor activity by affecting DNA binding and/or nuclear transport. A reporter plasmid containing two XREs was used to investigate the effects of phosphatase inhibitors on TCDD-dependent transcription by the Hepa-1 mouse liver cell line. The inhibitors calyculin A and okadaic acid caused two- to threefold increases in TCDD-dependent transcription at concentrations capable of selectively inhibiting protein phosphatase 1 and protein phosphatase 2A. The inhibitor cyclosporin A doubled TCDD-dependent transcription at a concentration capable of selectively inhibiting protein phosphatase 2B. All three of the phosphatase inhibitors increased TCDD-dependent transcription without affecting transcription in the absence of TCDD. Nuclear extracts were prepared from cells treated with concentrations of okadaic acid or cyclosporin A which substantially stimulated TCDD-dependent transcription. Neither of the inhibitors significantly increased the level of TCDD-dependent XRE binding in the extracts. GAL4-Arnt fusion proteins were used to further investigate whether the phosphatase inhibitors affected a step other than DNA binding. Okadaic acid treatment specifically increased the ability of a GAL4 fusion protein containing the Arnt PAS and transactivation domains to stimulate transcription. These results suggest that serine/threonine-specific protein phosphatases can act at a level subsequent to XRE binding to inhibit the ability of the Ah receptor/Arnt dimer to stimulate transcription.
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PMID:Inhibitors of serine/threonine-specific protein phosphatases stimulate transcription by the Ah receptor/Arnt dimer by affecting a step subsequent to XRE binding. 912 79

Previous studies from this laboratory identified a 28-kd nonreducible protein, liver-derived immunoinhibitory factor (LDIF) from the mouse liver. Isolation of this protein resulted in the co-purification of another unique protein called heat responsive protein 12 kd (Hrp12). In contrast to LDIF, Hrp12 was totally reducible to a protein of 12 kd suggesting a dimer. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) purification, followed by sequencing of an in situ cyanogen bromide digest of membrane bound Hrp12, yielded an internal 20-amino acid polypeptide. Degenerate oligonucleotides made from this peptide were used to screen a murine liver complementary DNA (cDNA) library. A 1240-bp cDNA clone was obtained with an internal 521-bp open reading frame (ORF). Sequence analysis of the 173-amino acid ORF of mouse Hrp12 showed a high degree of homology with a 99 amino acid rat liver-kidney perchloric acid-soluble protein (LKPS) and a 136-amino acid perchloric acid soluble rat protein (PSP). Transcripts for Hrp12 were mainly restricted to the liver and kidney in mouse and man. The protein was estimated to be approximately 0.8% of the total liver-soluble cytosolic protein. A zoo-blot probed at moderate stringency with labeled cDNA revealed a strong conservation of the gene in all of the mammalian species tested. Analysis of the protein structure of Hrp12 revealed motifs predicted to be targets for protein kinase C (PKC). More importantly, purified mouse Hrp12 could be phosphorylated in vitro with PKC. The protein had significant similarity to DnaK heat shock protein (Hsp)70 and contained a 54-amino acid stretch with sequence similarity to Hsp90. This prompted us to investigate the heat shock response of Hrp12. Isolated hepatocytes and hepatoma cells were exposed to different heat shock temperatures (39.5 degrees C, 42.5 degrees C, and 44.5 degrees C); and then total RNA was extracted and Northern analysis carried out. The message for this novel protein responded atypically to heat shock. Although the steady-state level of the message increased after heat shock, a marked oscillatory pattern was superimposed on it. In contrast, the steady-state levels of Hsp90 and Hsp70 messenger RNA (mRNA) were found to respond to heat shock in the expected manner. Finally, the amount of Hrp12 protein was also found to increase after heat shock in a manner that was consistent with heat-responsive proteins.
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PMID:Hrp12, a novel heat-responsive, tissue-specific, phosphorylated protein isolated from mouse liver. 914 40

Many B and T lymphocytes display a significant heterogeneity with respect to the subcellular distribution of the cytoskeletal protein spectrin and protein kinase C (PKC), both of which often can be found in a large cytoplasmic aggregate in these cell types. In addition to spectrin and PKC, we recently have reported that HSP70 is also a component of this lymphocyte aggregate. Moreover, these three proteins can undergo dynamic and reversible changes in their localization causing "assembly" of the aggregate in response to various conditions associated with lymphocyte activation, indicating that this naturally occurring aggregate structure is sensitive to activation status. We show here that the same changes in HSP70/spectrin/PKC localization induced by PKC activation also can be caused, in vitro and in vivo, by a mild hyperthermia exposure, as occurs during a natural fever (39.5-40 degrees C, 2-12 hr). This mild heat exposure also triggers the activation of PKC, a major heat shock response, and lymphocyte proliferation. The increase in PKC activity, HSP70-spectrin-PKC aggregate formation, and heat shock protein expression resulting from exposure to fever-like hyperthermia are all inhibited by calphostin C, a specific inhibitor of PKC. These data demonstrate that changes observed during lymphocyte activation could be induced by a mild hyperthermia exposure occurring during a normal febrile episode.
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PMID:Distribution of HSP70, protein kinase C, and spectrin is altered in lymphocytes during a fever-like hyperthermia exposure. 920 24

Protein kinase B (PKB, also named as Akt or RAC-protein kinase), that is activated by cellular stress such as heat shock and hyperosmotic treatment, was revealed to be activated by oxidative stress and by chemical stressors of CdCl2 and NaAsO2 by measuring the activity of the enzyme immunoprecipitated from the transfected COS-7 cells. Upon stress treatment, a 30-kDa phosphoprotein was co-immunoprecipitated with PKB from the cells metabolic labeled with [32P]orthophosphate. The phosphoprotein was identified as Hsp27, a small heat shock protein, by immunoblot analysis and co-immunoprecipitation. The association of Hsp27 was specific to PKB as the heat shock protein was not co-immunoprecipitated with other protein kinases such as protein kinase C and PKN. When the cells were treated with H2O2, PKB was activated gradually and the association of Hsp27 with PKB increased concurrently with the enhancement of PKB activity. In heat-shocked cells, activation of PKB and the association of Hsp27 were detected immediately after the treatment, and the association of the heat shock protein decreased while PKB kept stimulated activity when the cells were further incubated at 37 degrees C. These results suggest that Hsp27 is involved in the activation process of PKB in the signal transduction pathway of various forms of stress.
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PMID:Activation of protein kinase B (Akt/RAC-protein kinase) by cellular stress and its association with heat shock protein Hsp27. 923 90

The precise mechanism of the cardioprotective effect of ischemic preconditioning (IPC) is still unclear, although various mechanisms have been suggested, including activation of ATP-dependent potassium (KATP) channels by adenosine and protein kinase C as well as increased expression of heat shock protein (HSP). Increasing evidence suggests that lactate, which accumulates during IPC periods, can activate several of these "triggers" of preconditioning. We tested whether repeated exposure to lactate, producing tissue lactate concentrations similar to those during brief ischemic periods, could contribute to IPC benefits. Five isolated rat hearts were subjected to a previously reported IPC protocol composed of two 5-min ischemia-reperfusion cycles; another five hearts served as controls; and six hearts underwent a "lactate-preconditioning" protocol, consisting of two 5-min exposures to 15 mM lactate and two 5-min periods of reflow with a lactate-free buffer. Subsequently all hearts underwent 30 min of normothermic, total ischemia followed by 30 min of reflow at a constant perfusion pressure of 80 mmHg (1 mmHg = 133.3 Pa). Lactate exposure resulted in tissue lactate levels similar to those during ischemia in ischemia-preconditioned hearts (10.5 +/- 0.6 versus 10.5 +/- 1.2 mumol/g wet weight, mean +/- SEM). However, the recovery of left ventricular developed pressure (DevP) following 30 min of total ischemia was significantly higher in the IPC hearts than in either the control or lactate-exposed hearts, reaching 56.8 +/- 3.4, 14.2 +/- 6.8, and 9.5 +/- 3.6%, respectively, of the baseline values. There was no significant difference between lactate-preconditioned and control hearts. End-diastolic pressure (EDP) was significantly lower during reperfusion in IPC hearts than in lactate-exposed and control hearts, with no significant differences between the latter two groups (36.2 +/- 3.5, 82.0 +/- 2.9, and 81.2 +/- 8.5 mmHg, respectively). In contrast with the proposed hypothesis, repeated, transient lactate exposure resulting in tissue lactate levels similar to ischemic preconditioning did not improve contractile recovery after a prolonged ischemic period in this model.
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PMID:Repeated, transient lactate exposure does not "precondition" rat myocardium. 943 52

We investigated the activation of three subfamilies of mitogen-activated protein kinases (MAPKs), namely the stress-activated protein kinases/c-Jun N-terminal kinases (SAPKs/JNKs), the extracellularly responsive kinases (ERKs) and p38-MAPK, by oxidative stress as exemplified by H2O2 in primary cultures of neonatal rat ventricular myocytes. The 46 and 54 kDa species of SAPKs/JNKs were activated 5- and 10-fold, respectively, by 0.1 mM H2O2 (the maximally effective concentration). Maximal activation occurred at 15-30 min, but was still detectable after 2 h. Both ERK1 and ERK2 were activated 16-fold by 0.1 mM H2O2 with a similar time course to the SAPKs/JNKs, and this was comparable with their activation by 1 microM PMA, the most powerful activator of ERKs that we have so far identified in these cells. The activation of ERKs by H2O2 was inhibited by PD98059, which inhibits the activation of MAPK (or ERK) kinases, and by the protein kinase C (PKC) inhibitor, GF109203X. ERK activation was also inhibited by down-regulation of PMA-sensitive PKC isoforms. p38-MAPK was activated by 0.1 mM H2O2 as shown by an increase in its phosphorylation. However, maximal phosphorylation (activation) was more rapid (<5 min) than for the SAPKs/JNKs or the ERKs. We studied the downstream consequences of p38-MAPK activation by examining activation of MAPK-activated protein kinase 2 (MAPKAPK2) and phosphorylation of the MAPKAPK2 substrate, the small heat shock protein HSP25/27. As with p38-MAPK, MAPKAPK2 was rapidly activated (maximal within 5 min) by 0.1 mM H2O2. This activation was abolished by 10 microM SB203580, a selective inhibitor of certain p38-MAPK isoforms. The phosphorylation of HSP25/27 rapidly followed activation of MAPKAPK2 and was also inhibited by SB203580. Phosphorylation of HSP25/27 was associated with a decrease in its aggregation state. These data indicate that oxidative stress is a powerful activator of all three MAPK subfamilies in neonatal rat ventricular myocytes. Activation of all three MAPKs has been associated with the development of the hypertrophic phenotype. However, stimulation of p38-MAPK and the consequent phosphorylation of HSP25/27 may also be important in cardioprotection.
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PMID:Stimulation of multiple mitogen-activated protein kinase sub-families by oxidative stress and phosphorylation of the small heat shock protein, HSP25/27, in neonatal ventricular myocytes. 967 16


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