Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypercholesterolemia is one of the major risk factors for the development of cardiovascular disease. This study aims to elucidate the effect of gossypin on cholesterol metabolism in HepG2 cells. Results indicated that gossypin significantly reduced the total cholesterol concentration in a dose-dependent manner. There was a time- and dose-dependent increase in the expression of low-density lipoprotein receptor (LDLR) protein. However, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis, was not affected by gossypin. Moreover, gossypin had no effect on nuclear sterol regulatory element binding proteins (SREBP)-2 abundance. The activity of gossypin on LDLR expression was inhibited by the extracellular signal-regulated kinase (ERK) inhibitor PD98059. Western blotting analysis revealed that gossypin treatment dose- and time-dependently increased ERK activation and preceded the up-regulation of LDLR expression. Collectively, these new findings identify gossypin as a new hypocholesterolemic agent that up-regulates LDLR expression independent of SREBP-2 but is dependent on ERK activation.
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PMID:Gossypin up-regulates LDL receptor through activation of ERK pathway: a signaling mechanism for the hypocholesterolemic effect. 1900 37

As with Usher syndrome observed in humans, the two main phenotypes of the tubby mouse are progressive hearing loss and retinal degeneration. Yet, the mechanism underlying the tub-related cochlear degeneration is still unclear. The reduction/oxidation (redox) imbalance in the cell is related to many kinds of diseases. This study examined expressions of thioredoxin (Trx) and Trx reductase (TrxR), an important redox system in the cell, and the related upstream and downstream proteins of the Trx/TrxR in the tubby mouse cochlea. This report also examined the therapeutic effect of sulforaphane (SF) on the cochlear degeneration, which showed a protective effect on the tub-related retinal degeneration in our previous report. The results showed that the tub-mutation resulted in a significant suppression of Trx and TrxR expressions. Expression level of Nrf2 (NFE2 related factor 2), a transcription factor that regulates expression of Trx and TrxR and others, was also suppressed in the tubby mouse cochlea. Furthermore, a lowered level of activated extracellular signal-regulated kinase (p-ERK) was observed in the tubby mouse cochlea. In contrast, caspase-3 expression and activity were enhanced in the tubby mouse, suggesting apoptotic cell death. The tub-related molecular alterations in the cochlea were prevented by chronic treatment with SF. As a result, the SF-treatment significantly delayed the tub-related cochlear degeneration. Other unknown proteins may contribute to tubby-related degeneration because Nrf2 regulates many other antioxidants besides Trx/TrxR and sulforaphane did not prevent cochlear degeneration completely although it completely prevented alterations of Nrf2 and Trx/TrxR.
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PMID:Molecular mechanisms underlying cochlear degeneration in the tubby mouse and the therapeutic effect of sulforaphane. 1911 66

Neuroblastoma cell lines are commonly used as models to study neuronal differentiation, as they retain the capacity to differentiate into a neuronal-like phenotype. Receptor tyrosine kinase (RTK) signaling is essential for neuronal differentiation during development, and cholesterol-containing lipid-rafts are important for RTK signaling. Hydroxymethylglutaryl-coenzyme A reductase inhibitors of the statin family impair cholesterol biosynthesis and are in widespread clinical use for the treatment of cardiovascular diseases. It is of great clinical interest that statin treatment also correlates with a lower incidence of malignancies. We found that mevastatin triggered neurite outgrowth of neuroblastoma cells and examined the responsible signaling pathways. Treatment of Neuro2a cells with mevastatin for 24 hr induced neurite outgrowth associated with up-regulation of the neuronal marker protein NeuN. Interestingly, we found that mevastatin triggered phosphorylation of the key kinases epidermal growth factor receptor (EGFR), ERK1/2, and Akt/protein kinase B. Inhibition of EGFR, PI3K, and the mitogen-activated protein kinase cascade blocked mevastatin-induced neurite outgrowth. Moreover, add-back experiments of cell-permeable cholesterol precursors indicated that farnesylated and geranylgeranylated proteins play a major role in statin-induced neurite outgrowth. Taken together, our results provide the first mechanistic insight into statin-triggered signaling pathways that lead to neurite outgrowth in neuroblastoma cells. Surprisingly, we revealed that mevastatin triggered the phosphorylation of the EGFR and that this was because of the inhibition of farnesylated and geranylgeranylated proteins. We propose that members of the large family of farnesylated or geranylgeranylated small GTPases (such as Rabs or Rap1) regulating the trafficking and signaling of EGFR might be responsible for the statin-induced effects on EGFR signaling.
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PMID:Mevastatin-induced neurite outgrowth of neuroblastoma cells via activation of EGFR. 1922 73

3-Hydroxy 3-methylglutaryl coenzyme A reductase (HMG-CoAR) is the key and rate-limiting enzyme of cholesterol biosynthetic pathway. Although HMG-CoAR activity has already been related to the differentiation of some cellular lines there are no studies that analyze the role of HMG-CoAR, and the pathway it is involved with in a fully characterized muscle differentiation model. Thus, the aim of this work is to evaluate such role and delineate the pathway involved in foetal rat myoblasts (L6) induced to differentiate by insulin -- a standard and feasible model of the myogenic process. The results obtained by biochemical and morphological approaches demonstrate that (i) HMG-CoAR increase is crucial for differentiation induction, (ii) p21waf, whose increase is a necessary requisite for differentiation to occur, rises downstream HMG-CoAR activation, (iii) the main role of p38/MAPK as key regulator also for HMG-CoAR. Pathologies characterized by muscle degeneration might benefit from therapeutic programmes committed to muscle function restoration, such as modulation and planning myoblast differentiation. Thus, the important role of HMG-CoAR in muscular differentiation providing new molecular basis for the control of muscle development can help in the design of therapeutic treatment for diseases characterized by the weakening of muscular fibers and aging-related disorders (sarcopenia).
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PMID:3-hydroxy 3-methylglutaryl coenzyme A reductase increase is essential for rat muscle differentiation. 1938 10

The ubiquitous tripeptide glutathione (GSH) is an essential factor in many biological processes, thus its depletion has a major impact on cell function and survival. In this study, we examined regulation of GSH in cardiomyocytes under chronic oxidative stress elicited by myocardial infarction (MI). Cardiac dysfunction was induced in rats by coronary artery ligation, and experiments were conducted in myocytes isolated from non-infarcted left ventricle and septum after 6-8 weeks. Fluorescence microscopy studies using the probe monochlorobimane showed that [GSH] in myocytes from post-MI hearts was 42% less than in sham control hearts (P < 0.05). However, depleted GSH levels were normalized after 5-6 h by an insulin mimetic (bis-peroxovanadium-1,10-phenanthroline, bpV(phen); 10 micromol l(-1)) or by exogenous pyruvate (5 mmol l(-1)). The increase in [GSH] by bpV(phen) was partly inhibited by buthionine sulphoximine (BSO; 50 micromol l(-1)), a blocker of GSH synthesis, and by 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU; 100 micromol l(-1)), an inhibitor of glutathione disulphide reductase. By comparison, the effect of pyruvate was not altered by BSO but was completely blocked by BCNU. Studies using inhibitors of signalling cascades indicated that upregulation of [GSH] by bpV(phen) in myocytes from post-MI hearts was mediated by mitogen activated protein kinase/extracellular signal-regulated kinase kinase 1/2 and p38 mitogen-activated protein kinase but not by phosphatidylinositol 3-kinase. The effect of pyruvate was not altered by any kinase inhibitor tested. In cells loaded with the probe TEMPO-9-AC to monitor superoxide anion, baseline fluorescence was 2.3-fold greater in post-MI myocytes than in sham control myocytes (P < 0.05) and was markedly decreased by diphenyleneiodonium (30 micromol l(-1)), an inhibitor of NADPH oxidase, exogenous GSH (10 mmol l(-1)) or bpV(phen). In parallel studies, [GSH] in post-MI myocytes was also normalized by diphenyleneiodonium or exogenous GSH. These data show that GSH is differentially regulated by receptor tyrosine kinase-dependent and -independent agonists that maintain functional GSH levels necessary to neutralize excess generation of reactive oxygen species in the failing heart.
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PMID:Glutathione homeostasis in ventricular myocytes from rat hearts with chronic myocardial infarction. 1939 62

The isoprenoid alcohol farnesol is an effective inducer of cell cycle arrest and apoptosis in a variety of carcinoma cell types. In addition, farnesol has been reported to inhibit tumorigenesis in several animal models suggesting that it functions as a chemopreventative and anti-tumor agent in vivo. A number of different biochemical and cellular processes have been implicated in the growth-inhibitory and apoptosis-inducing effects of farnesol. These include regulation of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and CTP:phosphocholine cytidylyltransferase alpha (CCTalpha), rate-limiting enzymes in the mevalonate pathway and phosphatidylcholine biosynthesis, respectively, and the generation of reactive oxygen species. In some cell types the action of farnesol is mediated through nuclear receptors, including activation of farnesoid X receptor (FXR) and peroxisome proliferator-activated receptors (PPARs). Recent studies have revealed that induction of endoplasmic reticulum (ER) stress and the subsequent activation of the unfolded protein response (UPR) play a critical role in the induction of apoptosis by farnesol in lung carcinoma cells. This induction was found to be dependent on the activation of the MEK1/2-ERK1/2 pathway. In addition, farnesol induces activation of the NF-kappaB signaling pathway and a number of NF-kappaB target genes. Optimal activation of NF-kappaB was reported to depend on the phosphorylation of p65/RelA by the MEK1/2-MSK1 signaling pathway. In a number of cells farnesol-induced apoptosis was found to be linked to activation of the apoptosome. This review provides an overview of the biochemical and cellular processes regulated by farnesol in relationship to its growth-inhibitory, apoptosis-promoting, and anti-tumor effects.
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PMID:Molecular mechanisms involved in farnesol-induced apoptosis. 1952 Apr 95

Peroxiredoxins (PRXs) are thiol peroxidases associated with many cellular functions including proliferation, cell cycle, apoptosis, and differentiation. There is also increasing evidence that these ubiquitous antioxidant enzymes control H(2)O(2) signaling in eukaryotes. Here, we provide evidence that the LPS/TLR4 and the Th1 cytokine IFN-gamma pathways induce expression of PRX5, a potent peroxide and peroxynitrite reductase, in primary macrophages. Furthermore, deletion of TRIF, MyD88, or type I IFN receptor revealed that the LPS/TLR4-dependent increase in PRX5 expression is mediated by a TRIF-dependent/IFN-beta-independent pathway. IFN-gamma-dependent induction of the PRX5 gene was markedly reduced in MyD88(-/-) and TNF(-/-) macrophages. Moreover, addition of exogenous TNF allowed the recovery of full PRX5 expression in both MyD88(-/-) and TNF(-/-) cells stimulated with IFN-gamma, suggesting that basal TNF produced in an MyD88-dependent manner contributes to PRX5 induction. Downstream of the TLR pathways, we have explored the role of MAPK activation and found that p38 and JNK mainly contribute to PRX5 up-regulation in immunostimulated macrophages. Expression of PRX5 is thus responsive to innate immunity signals, and we propose that PRX5 is an additional host defense weapon of activated macrophages.
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PMID:Signaling events leading to peroxiredoxin 5 up-regulation in immunostimulated macrophages. 1954 Sep 14

ASK1 cysteine oxidation allows JNK activation upon oxidative stress. Trx1 negatively regulates this pathway by reducing the oxidized cysteines of ASK1. However, precisely how oxidized ASK1 is involved in JNK activation and how Trx1 regulates ASK1 oxidoreduction remains elusive. Here, we describe two different thiol reductase activities of Trx1 on ASK1. First, in H(2)O(2)-treated cells, Trx1 reduces the various disulfide bonds generated between cysteines of ASK1 by a rapid and transient action. Second, in untreated cells, Trx1 shows a more stable thiol reductase activity on cysteine 250 (Cys250) of ASK1. After H(2)O(2) treatment, Trx1 dissociates from Cys250, which is not sufficient to activate the ASK1-JNK pathway. Indeed, in untreated cells, a Cys250 to alanine mutant of ASK1 (C250A), which cannot bind Trx1, does not constitutively activate JNK. On the other hand, in H(2)O(2)-treated cells, this mutant (C250A) fails to activate JNK and does not induce apoptosis, although it remains fully phosphorylated on Threonine 838 (Thr838) in its activation loop. Overall, our data show that Cys250 is essential for H(2)O(2)-dependent signaling downstream from ASK1 but at a step subsequent to the phosphorylation of ASK1 Thr838. They also clarify the thiol reductase function of Trx1 on ASK1 activity.
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PMID:REDOX reaction at ASK1-Cys250 is essential for activation of JNK and induction of apoptosis. 1957 Sep 11

Expression of functionally active thrombomodulin (TM) on endothelial cells is critical for vascular thromboresistance. 3-Hydroxyl-3-methyl coenzyme A reductase inhibitors (statins) can protect the vasculature from inflammation and atherosclerosis caused by cholesterol-dependent and cholesterol-independent mechanisms. In the present study, the effects of atorvastatin on TM expression in the aorta of cholesterol-fed rabbits and in TNFalpha-treated human aortic endothelial cells (HAECs) were investigated. When rabbits were fed a 0.5% cholesterol diet with and without supplementation with atorvastatin for 9 weeks, the neointimal area in the thoracic aorta of the atorvastatin-treated group was significantly reduced and there was significant induction of TM protein expression. In HAECs, TNFalpha treatment decreased the expression of TM in a time- and dose-dependent manner and atorvastatin pretreatment upregulated the expression of TM mRNA and protein in HAECs with or without TNFalpha treatment. Atorvastatin also inhibited monocyte adhesion to control and TNFalpha-treated HAECs via TM expression. ERK1/2 phosphorylation was significantly reduced by 24 h pretreatment with atorvastatin, whereas TNFalpha increased the phosphorylation of the MAPKs, p38, JNK, and ERK1/2. Blocking the transcriptional activation of NF-kappaB and nuclear translocation of NF-kappaB p65 prevented the TNFalpha-induced downregulation of TM. Atorvastatin regulated TM expression in control and TNFalpha-treated HAECs by inhibiting the activation of ERK and NF-kappaB. The increase in endothelial TM activity in response to atorvastatin constitutes an important pleiotropic effect of this commonly used compound and may be of clinical significance in cardiovascular disorders in which deficient endothelial TM plays a pathophysiological role.
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PMID:Atorvastatin induces thrombomodulin expression in the aorta of cholesterol-fed rabbits and in TNFalpha-treated human aortic endothelial cells. 1960 62

Cytosolic 2-cys peroxiredoxin (2-cysPrx) exhibiting thioredoxin-dependent hydroperoxide reductase activity has been demonstrated to be involved in a number of signaling processes, such as receptor tyrosine kinase and MAP kinase activation. However, its role in the cell death pathway has yet to be elucidated. Here we show that cytosolic 2-cysPrx suppresses the TNF-alpha-induced apoptosis of human cervical cancer cells in a caspase-8-dependent manner. The HeLa cervical cancer cells expressing a dominant negative mutant (DN) of a cytosolic 2-cysPrx manifested remarkable increase in intracellular reactive oxygen species level, which was counteracted by catalase administration, and apoptotic cell death induced by combined treatment of TNF-alpha and cycloheximide compared to the control (CT) cells. Similarly, the DN cells were also susceptible to apoptosis induced by the TNF-related apoptosis-inducing ligand. The apoptosis enhanced by DN expression was shown to be dependent on a typical FADD/caspase pathway. The DN cells undergoing apoptosis showed enhanced caspase-8 and -3 activations, as compared to the CT cells. In contrast, there was no difference observed in the sustained JNK activation between CT and DN cells. Thus, this study illustrates that intracellular reactive oxygen species regulated by cytosolic 2-cysPrx is involved in the TNF-alpha-induced apoptotic cell death via controlling caspase activation.
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PMID:Protective role of cytosolic 2-cys peroxiredoxin in the TNF-alpha-induced apoptotic death of human cancer cells. 1964 26


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