Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.3.5.1 (succinate dehydrogenase)
 8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 78-kDa glucose-regulated protein (GRP78) is ubiquitously expressed in many cell types. Its promoter contains multiple protein-binding sites and functional elements. In this study we examined a high affinity protein-binding site spanning bp -198 to -180 of the rat grp78 promoter, using nuclear extracts from both B-lymphoid and HeLa cells. This region contains a sequence TGACGTGA which, with the exception of one base, is identical to the cAMP-response element (CRE). Site-directed mutagenesis reveals that this sequence functions as a major basal level regulatory element in hamster fibroblast cells and is also necessary to maintain high promoter activity under stress-induced conditions. By gel mobility shift analysis, we detect two specific protein complexes. The major specific complex I, while immunologically distinct from the 42-kDa CRE-binding protein (CREB), binds most strongly to the grp site, but also exhibits affinity for the CRE consensus sequence. As such, complex I may consist of other members of the CREB/activating transcription factor protein family. The minor specific complex II consists of CREB or a protein antigenically related to it. A nonspecific complex III consists of the Ku autoantigen, an abundant 70- to 80-kDa protein complex in HeLa nuclear extracts. By cotransfection experiments, we demonstrate that in F9 teratocarcinoma cells, the grp78 promoter can be transactivated by the phosphorylated CREB or when the CREB-transfected cells are treated with the calcium ionophore A23187. The differential regulation of the grp78 gene by cAMP in specific cell types and tissues is discussed.
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PMID:A binding site for the cyclic adenosine 3',5'-monophosphate-response element-binding protein as a regulatory element in the grp78 promoter. 183 91

We have demonstrated that treatment with 200 nM okadaic acid (OA) for 1 h followed by a 15-min heat shock (HS) at 45 degrees C (termed OA-->HS treatment) leads to a rapid transactivation of grp78, the gene for the 78-kDa glucose-regulated protein, in 9L rat brain tumor cells. The level of Grp78 mRNA rose 15-fold in 60 min after the combined treatment. Nuclear extracts from cells subjected to OA-->HS treatment, compared to those of treatment with OA or HS alone, exhibited an increased binding activity toward an oligonucleotide probe containing the cAMP-responsive element-like (CRE-like, TGACGTGA) regulatory element in electrophoretic mobility shift assays (EMSA). The binding resulted in the formation of two protein-EMSA probe complexes exhibiting different association and dissociation rates in kinetic studies. The protein factors in the upper band (complex I) and lower band (complex II) were identified as the activating transcription factor-2 (ATF-2) and the CRE binding factor 1 (CREB-1), respectively, by antibody interference assays. In addition, the identity of CREB-1 was confirmed by supershift analysis. The binding activity, as well as the transactivation of the grp78 gene, can be abolished by a 1-h treatment with the cAMP-dependent protein kinase (PKA) inhibitor but not with protein kinase C or Ca2+/calmodulin-dependent protein kinase II inhibitors. Accumulation of steady-state level of ATF-2 was observed and was also modulated by treatment with H-89, a PKA inhibitor. From these results, we conclude that the CRE-like element plays an important role in the rapid transactivation of the grp78 gene and that the PKA signaling pathway is involved. In addition, PKA-mediated transcriptional regulation of grp78 in OA-->HS treatment is through regulation of protein phosphorylation as well as de novo synthesis of ATF-2.
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PMID:Rapid induction of the Grp78 gene by cooperative actions of okadaic acid and heat-shock in 9L rat brain tumor cells--involvement of a cAMP responsive element-like promoter sequence and a protein kinase A signaling pathway. 931 Mar 69

The present study was designed to investigate the effect of previous heat shock treatment on the mitochondria function of the heart during a cecal ligation and puncture (CLP)-induced sepsis model. Rats of the heated group were heated by whole-body hyperthermia 24 h before the CLP operation. Cardiac mitochondria were freshly collected 9 and 18 h after CLP, indicating early and late sepsis, respectively. The expressions of heat shock protein 72 (Hsp72), glucose-regulated protein 75 (Grp75), and mitochondrial complexes I, II, III, and IV were evaluated by Western blot and immunochemical analysis. Enzyme activities of NADH cytochrome c reductase (NCCR), succinate cytochrome c reductase (SCCR), and cytochrome c oxidase (CCO) were measured after the reduction or oxidation of cytochrome c using a spectrophotometer. The results showed that the ATP content in the heart significantly declined during late sepsis, whereas heat shock treatment reversed this declination. The enzyme activities of NCCR, SCCR, and CCO were apparently suppressed during late stage of sepsis. The protein expressions of mitochondrial complex II and complex IV and Grp75 were also down-regulated during sepsis. Previously treated by heat shock, late-sepsis rats emerged with a high preservation of mitochondrial respiratory chain enzymes, both the protein amount and enzyme activity. Aspects of morphology were observed by electron microscopy, while heat shock treatment revealed the attenuation of cardiac mitochondrial damage induced by sepsis. In conclusion, structural deformity and the decrease of respiratory chain enzyme activity in mitochondria and its leading to a decline of ATP content are highly correlated with the deterioration of cardiac function during sepsis, and heat shock can reverse adverse effects, thus achieving a protective goal.
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PMID:Heat shock pretreatment prevents cardiac mitochondrial dysfunction during sepsis. 1292 1

Hyperhomocysteinemia (HHcy) is a critical independent risk factor for cardiovascular diseases. However, to date, no satisfactory strategies to prevent HHcy exist. Since homocysteine (Hcy) and endogenous H2S are both metabolites of sulfur-containing amino acids, we aimed to investigate whether a metabolic product of Hcy and H2S, may antagonize in part the cardiovascular effects of Hcy. In the HHcy rat model injected subcutaneously with Hcy for 3 weeks, H2S levels and the H2S-generating enzyme cystathionine gamma lyase (CSE) activity in the myocardium were decreased. The intraperitoneal injection of H2S gas saturation solution significantly reduced plasma total Hcy (tHcy) concentration and decreased lipid peroxidation formation (i.e., lowered manodialdehyde and conjugated diene levels in myocardia and plasma). The activities of myocardial mitochondrial respiratory enzymes succinate dehydrogenase, cytochrome oxidase, and manganese superoxide dismutase, related to reactive oxygen species metabolism, were significantly dysfunctional in HHcy rats. The H2S administration restored the level of enzyme activities and accelerated the scavenging of H2O2 and superoxide anion generated by Hcy in isolated mitochondria. The H2S treatment also inhibited the expression of glucose-regulated protein 78, a marker of endoplasmic reticulum (ER) stress, induced by Hcy in vivo and in vitro. Thus, HHcy impaired the myocardial CSE/H2S pathway, and the administration of H2S protected the myocardium from oxidative and ER stress induced by HHcy, which suggests that an endogenous metabolic balance of sulfur-containing amino acids may be a novel strategy for treatment of HHcy.
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PMID:Hydrogen sulfide inhibits myocardial injury induced by homocysteine in rats. 1807 43