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)

An inverse relationship exists between kallistatin levels and salt-induced oxidative stress in Dahl-salt sensitive rats. We further investigated the role of kallistatin in inhibiting inflammation and fibrosis through antioxidative stress in Dahl-salt sensitive rats and cultured renal cells. High-salt intake in Dahl-salt sensitive rats induced elevation of thiobarbituric acid reactive substances (an indicator of lipid peroxidation), malondialdehyde levels, reduced nicotinamide-adenine dinucleotide phosphate oxidase activity, and superoxide formation, whereas kallistatin gene delivery significantly reduced these oxidative stress parameters. Kallistatin treatment improved renal function and reduced kidney damage as evidenced by diminished proteinuria and serum urea nitrogen levels, glomerular sclerosis, tubular damage, and protein cast formation. Kallistatin significantly decreased interstitial monocyte-macrophage infiltration and the expression of tumor necrosis factor-alpha, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1. Kallistain also reduced collagen fraction volume and the deposition and expression of collagen types I and III. Renal protection by kallistatin was associated with increased NO levels and endothelial NO synthase expression and decreased p38 mitogen-activated protein kinase, extracellular signal-regulated kinase phosphorylation, and transforming growth factor-beta1 expression. Moreover, kallistatin attenuated tumor necrosis factor-alpha-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression via inhibition of reactive oxygen species formation and p38 mitogen-activated protein kinase and nuclear factor-kappaB activation in cultured proximal tubular cells. Kallistatin inhibited fibronectin and collagen expression by suppressing angiotensin II-induced reactive oxygen species generation and transforming growth factor-beta1 expression in cultured mesangial cells. These combined findings reveal that kallistatin is a novel antioxidant, which prevents salt-induced kidney injury, inflammation, and fibrosis by inhibiting reactive oxygen species-induced proinflammatory cytokine and transforming growth factor-beta1 expression.
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PMID:Salutary effect of kallistatin in salt-induced renal injury, inflammation, and fibrosis via antioxidative stress. 1839 Oct 98

In human glioblastoma multiforme (GBM), RAS activity is upregulated in the majority of the tumors. Furthermore, the levels of phospho-mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK), a downstream effector of RAS, are also increased. In mice, activated KRas cooperates with the loss of INK4a-ARF locus or with activated Akt to induce gliomas, confirming an important role for this pathway in glioma biology. However, to correctly target therapies against the RAS signaling pathway, it is necessary to identify the effectors that contribute to RAS-mediated gliomagenesis. In this study, we investigated the contribution of RAF signaling in glioma oncogenesis. We find that the levels of RAF-1 and BRAF proteins and RAF kinase activity are increased in human GBM samples. We confirm the importance of this finding by demonstrating a causal role for a constitutively active Raf-1 mutant in glioma formation in mice. Specifically, we find that activated Raf-1 cooperates with Arf loss or Akt activation to generate gliomas similar to activated KRas under the same conditions. Our study suggests that the oncogenic effect of KRas in glioma formation may be transduced at least in part through Raf signaling and that therapeutic targeting of this pathway may be beneficial in glioma treatment.
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PMID:Constitutive activation of Raf-1 induces glioma formation in mice. 1847 67

The present study was undertaken to determine whether hypotonicity regulates the aquaporin-2 (AQP-2) gene in vitro. The 5'-flanking region of the AQP-2 gene contains the tonicity-response enhancer (TonE) promoter located between -570 and -560 bp, and another distinct hypertonicity-responsive region between -6.1 and -4.3 kb of the AQP-2 gene. The 5'-flanking region of murine AQP-2 gene up to -9.5 kb was cloned into a luciferase (Luc) reporter plasmid. The constructs, which have TonE and/or the hypertonicity-responsive region, together with the murine AQP-2 gene, were co-transfected into murine IMCD(3) cells. When the cells were co-transfected with the construct containing more than 1.1 kb of the 5'-flanking region of murine AQP-2 gene (-9.5AQP2, -6.1AQP2 and -1.1AQP2) and the AQP-2 gene, 24 h exposure to 5 micromol l(-1) dibutyryl cAMP (DBcAMP) significantly increased the Luc activity by 2.3-fold in the isotonic medium (300 mosmol kg(-1)). In the hypotonic medium (225 mosmol kg(-1)), basal activity was not altered, and the response of Luc activity to 24 h exposure to 5 micromol l(-1)DBcAMP was abolished. Similar findings were obtained in isosmotic, urea-supplemented medium (estimated tonicity, 225 mosmol kg(-1)). The response of Luc activity to 5 micromol l(-1) DBcAMP in the hypotonic medium was not affected in cells either transfected with 0.36 kb of the 5'-flanking region of AQP-2 or co-transfected with -1.1AQP2 and a dominant-negative TonE binding protein (pDNTonEBP). Pre-incubation of cells with 1 micromol l(-1) SP600125, an inhibitor of c-Jun N-terminal kinase (JNK), restored the response of Luc activity to 5 micromol l(-1) DBcAMP under hypotonic conditions. These findings may indicate that hypotonicity reduces the cAMP-induced AQP-2 promoter activity mediated via TonE by activating JNK kinase.
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PMID:Hypotonicity reduces the activity of murine aquaporin-2 promoter induced by dibutyryl cAMP. 1851 71

Chronic allograft nephropathy (CAN), the most common cause of late kidney allograft failure, is not effectively prevented by immunosuppressive regimens. Activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) via MEK mediates actions of various growth factors, including transforming growth factor (TGF)-beta1, which plays a key role in CAN. Hence, we tested the therapeutic potential of MEK-ERK1/2 signaling disruption to prevent CAN. Kidneys from C57BL/6J (H-2(b)) mice were transplanted to bilaterally nephrectomized BALB/c (H-2(d)) mice. At 14 days after transplantation, the recipients were subjected to 28 days of treatment with the MEK inhibitor CI-1040. All six CI-1040-treated allografts survived, while two of seven grafts in the vehicle-treated group were lost. At the end of the experiment, the function and structure of grafts in the CI-1040-treated group were significantly preserved, as indicated by lower levels of serum creatinine or blood urea nitrogen than in the vehicle-treated group [30 +/- 6 vs. 94 +/- 39 microM creatinine (P = 0.0015) and 22 +/- 8 vs. 56 +/- 25 mM BUN (P = 0.0054)] and reduced CAN in the CI-1040-treated group compared with vehicle controls (CAN score = 4.2 vs. 10.3, P = 0.0119). The beneficial effects induced by CI-1040 were associated with reduction of ERK1/2 phosphorylation and TGFbeta1 levels in grafts. Also, CI-1040 potently suppressed not only TGFbeta biosynthesis in kidney cell cultures but also antiallograft immune responses in vitro and in vivo. Our data suggest that interference of MEK-ERK1/2 signaling with a pharmacological agent (e.g., CI-1040) has therapeutic potential to prevent CAN in kidney transplantation.
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PMID:Reduction of chronic allograft nephropathy by inhibition of extracellular signal-regulated kinase 1 and 2 signaling. 1861 19

Myo-inositol (MI) is a compatible osmolyte used by cells to compensate for changes in the osmolarity of their surrounding milieu. In kidney, the basolateral Na(+)-MI cotransporter (SMIT1) and apical SMIT2 proteins are homologous cotransporters responsible for cellular uptake of MI. It has been shown in the Madin-Darby canine kidney (MDCK) cell line that SMIT1 expression was under the control of the tonicity-sensitive transcription factor, tonicity-responsive enhancer binding protein (TonEBP). We used an MDCK cell line stably transfected with SMIT2 to determine whether variations in external osmolarity could also affect SMIT2 function. Hyperosmotic conditions (+200 mosM raffinose or NaCl but not urea) generated an increase in SMIT2-specific MI uptake by three- to ninefold in a process that required protein synthesis. Using quantitative RT-PCR, we have determined that hyperosmotic conditions augment both the endogenous SMIT1 and the transfected SMIT2 mRNAs. Transport activities for both SMIT1 and SMIT2 exhibited differences in their respective induction profiles for both their sensitivities to raffinose, as well as in their time course of induction. Application of MG-132, which inhibits nuclear translocation of TonEBP, showed that the effect of osmolarity on transfected SMIT2 was unrelated to TonEBP, unlike the effect observed with SMIT1. Inhibition studies involving the hyperosmolarity-related MAPK suggested that p38 and JNK play a role in the induction of SMIT2. Further studies have shown that hyperosmolarity also upregulates another transfected transporter (Na(+)-glucose), as well as several endogenously expressed transport systems. This study shows that hyperosmolarity can stimulate transport in a TonEBP-independent manner by increasing the amount of mRNA derived from an exogenous DNA segment.
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PMID:Effects of hyperosmolarity on the Na+ -myo-inositol cotransporter SMIT2 stably transfected in the Madin-Darby canine kidney cell line. 1865 Feb 62

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm in the gastrointestinal tract and is associated with mutations of the KIT or PDGFRA gene. In addition, other genetic events are believed to be involved in GIST tumorigenesis. Cytogenetic aberrations associated with these tumors thus far described include loss of 1p, 13q, 14q, or 15q, loss of heterozygosity of 22q, numeric chromosomal imbalances, and nuclear/mitochondrial microsatellite instability. Molecular genetic aberrations include loss of heterozygosity of p16(INK4A) and p14(ARF), methylation of p15(INK4B), homozygous loss of the Hox11L1 gene, and amplification of C-MYC, MDM2, EGFR1, and CCND1. GISTs in patients with neurofibromatosis type 1 appear to lack the KIT and PDGFRA mutations characteristic of GISTs and may have a different pathogenetic mechanism. Gene mutations of KIT or PDGFRA are critical in GISTs, because the aberrant versions not only are correlated with the specific cell morphology, histologic phenotype, metastasis, and prognosis, but also are the targets of therapy with imatinib and other agents. Furthermore, specific mutations in KIT and PDGFR appear to lead to differential drug sensitivity and may in the future guide selection of tyrosine kinase inhibitors. Activation of the receptor tyrosine kinases involves a signal transduction pathway whose components (mitogen-activated protein kinase, AKT, phosphoinositide 3-kinase, mammalian target of rapamycin, and RAS) are also possible targets of inhibition. A new paradigm of classification, integrating the standard clinical and pathological criteria with molecular aberrations, may permit personalized prognosis and treatment.
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PMID:Genetic aberrations of gastrointestinal stromal tumors. 1867 Dec 47

Herein, we describe three kinds of 2-DE using phosphate-affinity PAGE for the analysis of phosphoprotein isotypes. The first dimension is a urea-PAGE, IEF/NEPHGE, or SDS-PAGE, which are widely used. The second dimension is a phosphate-affinity SDS-PAGE using a phosphate-binding tag molecule, Phos-tag (Mn(2+)-Phos-tag SDS-PAGE). The first 2-D procedure coupling urea-PAGE and Mn(2+)-Phos-tag SDS-PAGE was applied to the separation of beta-casein phosphoisotypes. A typical protein sample containing multiple phosphoisotypes from beta-casein (with five phosphorylation sites) was prepared by partial dephosphorylation with alkaline phosphatase. The second procedure coupling IEF/NEPHGE and Mn(2+)-Phos-tag SDS-PAGE was applied to the separations of phosphoisotypes of caseins and in vitro kinase reaction products of Tau. The third procedure coupling normal SDS-PAGE and Mn(2+)-Phos-tag SDS-PAGE was applied to the separation of A431 cell lysates before and after stimulation with an epidermal growth factor. This procedure followed by immunoblotting with anti-mitogen-activated protein kinase(MAPK) and anti-Shc antibodies demonstrated the detection of phosphoisotypes in each protein isoform of MAPK1/2 (44 and 42 kDa) and Shc (66, 52, and 46 kDa) after the stimulation. By these novel 2-D procedures, the separations of phosphoprotein isotypes should be improved relative to those by current gel electrophoresis methods, including 1-D Mn(2+)-Phos-tag SDS-PAGE.
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PMID:Two-dimensional phosphate-affinity gel electrophoresis for the analysis of phosphoprotein isotypes. 1915 64

Embryonic stem cells are immortalized cells whose proliferation rate is comparable to that of carcinogenic cells. To study the expression of embryonic stem cell genes in primary cells, genetic screening was performed by infecting mouse embryonic fibroblasts (MEFs) with a cDNA library from embryonic stem cells. Cold-inducible RNA-binding protein (CIRP) was identified due to its ability to bypass replicative senescence in primary cells. CIRP enhanced extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation, and treatment with an MEK inhibitor decreased the proliferation caused by CIRP. In contrast to CIRP upregulation, CIRP downregulation decreased cell proliferation and resulted in inhibition of phosphorylated ERK1/2 inhibition. This is the first evidence that ERK1/2 activation, through the same mechanism as that described for a Val12 mutant K-ras to induce premature senescence, is able to bypass senescence in the absence of p16(INK4a), p21(WAF1), and p19(ARF) upregulation. Moreover, these results show that CIRP functions by stimulating general protein synthesis with the involvement of the S6 and 4E-BP1 proteins. The overall effect is an increase in kinase activity of the cyclin D1-CDK4 complex, which is in accordance with the proliferative capacity of CIRP MEFs. Interestingly, CIRP mRNA and protein were upregulated in a subgroup of cancer patients, a finding that may be of relevance for cancer research.
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PMID:Cold-inducible RNA-binding protein bypasses replicative senescence in primary cells through extracellular signal-regulated kinase 1 and 2 activation. 1915 77

Chronic kidney disease is often complicated by uremic cardiomyopathy that consists of left ventricular hypertrophy and interstitial fibrosis. It is thought that hypertension and volume overload are major causes of this disease, but here we sought to identify additional mechanisms using a mouse model of chronic renal insufficiency. Mice with a remnant kidney developed an elevated blood urea nitrogen by 1 week, as expected, and showed progressive cardiac hypertrophy and fibrosis at 4 and 8 weeks even though their blood pressures were not elevated nor did they show signs of volume overload. Cardiac extracellular signal-regulated kinase (ERK) was activated in the uremic animals at 8 weeks. There was also an increased phosphorylation of S6 kinase, which is often mediated by activation of the mammalian target of rapamycin (mTOR). To test the involvement of this pathway, we treated these uremic mice with rapamycin and found that it reduced cardiac hypertrophy. Reduction of blood pressure, however, by hydralazine had no effect. These studies suggest that uremic cardiomyopathy is mediated by activation of a pathway that involves the mTOR pathway.
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PMID:Uremic cardiac hypertrophy is reversed by rapamycin but not by lowering of blood pressure. 1933 17

Acute renal failure (ARF) is mainly characterized by acute tubular necrosis. No significant change was found for mortality rates over the past few decades despite significant advances in supportive care. In recent years, great effort has been focused on traditional and herbal medicine, which is much less toxic than those agents conventionally used and which is nowadays considered as a novel therapeutic agent for ARF. However, the effect of ginsenosides (GS) administered orally on ARF has not been reported yet and little is known about its cellular and molecular mechanism. The purpose of the study is to investigate the protective effect of ginsenoside in rats with ARF on the changes of tyrosine hydroxylase immunoreactivity (TH-IR) as well as on the involvement of mitogen-activated protein kinases (MAPK) in the locus coeruleus. In our assay, glycerol-induced acute renal failure in rats was employed to study the protective effects of ginsenoside. Our results indicated that the treatment of ARF rats with ginsenosides for 48 h significantly reduced the serum blood urea nitrogen, creatinine level, and lipid peroxidation, restored the GSH level and the normal renal morphology. Immunohistochemistry showed that an obvious increase of TH-IR was further enhanced in ARF+GS group. The same effect was also observed in the changes of p-ERK1/2-IR in the locus coeruleus. Our results suggest that ginsenoside administered orally may have a strong renal protective effect against glycerol-induced ARF, and ginsenoside can also activate the brain catecholaminergic neurons in the locus coeruleus. Our future attention will be focused to the question whether there is a correlation between the renal protective effect of ginsenosides against acute renal failure and the activation of tyrosine hydroxylase in the locus coeruleus.
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PMID:Protective effect of ginsenoside against acute renal failure and expression of tyrosine hydroxylase in the locus coeruleus. 1924 9


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