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

---

Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cisplatin induces acute renal injury in part by increasing the production of TNF-alpha. However, the mechanism by which cisplatin increases renal TNF-alpha expression is not known. The transcription, translation, and stability of TNF-alpha mRNA are sites of regulation of TNF-alpha production. This study investigated the effects of cisplatin on TNF-alpha mRNA stability and the role of MAP kinases in this process in cultured renal proximal tubule cells. Cisplatin increased the expression of TNF-alpha mRNA by proximal tubule cells in a time- and dose-dependent manner, as well as activated p42/44 ERK kinase, p38 MAP kinase, and JNK in a dose-dependent manner. The inhibition of these pathways reduced TNF-alpha expression significantly. Cisplatin also increased the stability of TNF-alpha mRNA, but this effect was not mediated by MAP kinases and did not require the synthesis of a new protein. The treatment of cells with cisplatin induced the formation of complexes of cytosolic proteins and the AU-rich region of the TNF-alpha 3'UTR. These results are consistent with the view that cisplatin increases TNF-alpha mRNA stability in a MAP kinase-independent manner. The stabilization of TNF-alpha mRNA by cisplatin may involve the binding of certain proteins to AU-rich regions in the 3'UTR.
...
PMID:Cisplatin increases TNF-alpha mRNA stability in kidney proximal tubule cells. 1705 Feb 42

Acid addition to the body activates a series of homeostatic responses, one example of which is activation of NHE3, the proximal tubule Na(+)/H(+) antiporter. Feeding acid to rats increases apical membrane NHE3 abundance. Similarly, addition of acid to the media of OKP cells, a proximal tubule cell line, leads to an increase in apical membrane NHE3 activity that is due to increased trafficking of NHE3 to the apical membrane, and increased NHE3 mRNA and protein expression. Endothelins also increase NHE3 activity by inducing trafficking of NHE3 to the apical membrane, an effect mediated by the ET(B), but not the ET(A) receptor. Receptor specificity resides in the C-terminal loop and the second intracellular loop of the ET(B) receptor. In addition, the ET(B) receptor is required for acid signaling. An acid-induced signaling cascade has been defined that includes Pyk2, c-Src, ERK, c-fos, c-jun, and endothelin expression.
...
PMID:Dietary acid, endothelins, and sleep. 1706 Sep 81

Kidney injury molecule-1 (KIM-1) is markedly upregulated in renal proximal tubule cells by stimuli that promote dedifferentiation, including ischemic or toxic injury, as well as in cases of tubulointerstitial disease, polycystic kidney disease, and renal cell carcinoma. Structurally, KIM-1 possesses a single transmembrane domain and undergoes membrane-proximal cleavage, which leads to the release of soluble KIM-1 ectodomain into the urine. Urinary KIM-1 ectodomain is a promising sensitive and specific biomarker for acute kidney injury in humans, and therefore it is important to determine what regulates KIM-1 shedding. We found that constitutive cleavage of KIM-1 is mediated by ERK activation, and that cleavage is accelerated by p38 MAP kinase activation. After cleavage, a 14-kD membrane-bound fragment of KIM-1, which contains two highly conserved tyrosine residues, was tyrosine-phosphorylated. Mutagenesis studies demonstrated that the juxtamembrane secondary structure, not the primary amino acid sequence, was critical to the cleavage of KIM-1.
...
PMID:Shedding of the urinary biomarker kidney injury molecule-1 (KIM-1) is regulated by MAP kinases and juxtamembrane region. 1789 36

We have previously shown that ouabain and other cardiotonic steroids interact with the plasmalemmal Na/K-ATPase and cause a time and dose dependent endocytosis of the Na/K-ATPase. This endocytosis is demonstrable using fluorescence imaging as well as conventional biochemical and biophysical cell separation methods. In proximal tubule cells, this process appears to regulate the density of basolateral Na/K-ATPase expression directly as well as indirectly modulate transepithelial sodium transport. Work with genetic manipulations, as well as pharmacological agents with cell culture models, have demonstrated that the cardiotonic steroid stimulated endocytosis of the plasmalemmal Na/K-ATPase requires caveolin and clathrin as well as the activation of c-Src, transactivation of the EGFR and activation of PI3K. Interestingly c-Src, EGFR and ERK1/2 all appear to be endocytosed along with the plasmalemmal Na/K-ATPase. These observations suggest a close analogy between a subset of plasmalemmal Na/K-ATPase and signaling companions with conventional receptor tyrosine kinases. While further studies are necessary to delineate the role of this endocytosis in the generation as well as the limit of signal transduction through the Na/K-ATPase signal cascade, we propose that it has an important role in the regulation of renal sodium handling as well as other important processes.
...
PMID:Regulation of sodium pump endocytosis by cardiotonic steroids: Molecular mechanisms and physiological implications. 1796 98

In hypocalcaemia, elevated parathyroid hormone transitorily down-regulates the kidney vitamin D receptor, which returns to normal levels with the rise in serum extracellular calcium [Ca(2+)](e). In this study, we investigated the mechanism that underlies VDR increase in kidney in association with elevated [Ca(2+)](e). Examination of MAP kinase signals in a proximal tubule human kidney (HK-2G) epithelial cell line showed that treatment of [Ca(2+)](e) in the culture medium elevated phosphorylation of both ERK and p38 MAPKs. Blockade of p38 phosphorylation with SB203580 or SB202190 in turn abolished [Ca(2+)](e)-mediated VDR protein increase, while treatment with PD98059 and U0126, specifically blocked ERK phosphorylation, but had no effect on VDR stimulation by [Ca(2+)](e). Furthermore, SB203580 treatment potently repressed [Ca(2+)](e)-mediated activation of VDR promoter. We also demonstrate that si-RNA knock down of p38alpha completely diminished high [Ca(2+)](e)-mediated VDR induction. Direct CaSR involvement was demonstrated by using an si-RNA of CaSR that impeded [Ca(2+)](e)-mediated induction of VDR. In conclusion, a high extracellular [Ca(2+)](e) concentration in the physiological range is capable of directly increasing renal proximal VDR expression, and the induction mechanism requires activation of the CaSR and signal mediation by the p38alpha MAP kinase pathway.
...
PMID:Extracellular calcium-sensing receptor activation induces vitamin D receptor levels in proximal kidney HK-2G cells by a mechanism that requires phosphorylation of p38alpha MAPK. 1797 68

Several volatile anesthetics, including sevoflurane, protect against renal ischemia-reperfusion injury in vivo by reducing necrosis and inflammation. Furthermore, in cultured renal tubule cells, sevoflurane directly induced the phosphorylation of the cytoprotective kinases (ERK and Akt), upregulated 70-kDa heat shock protein (HSP70), and attenuated nuclear translocation of the proinflammatory transcription factor NF-kappaB. It has been shown that sevoflurane increases the release of transforming growth factor-beta1 (TGF-beta1) in human proximal tubule (HK-2) cells via externalization of plasma membrane phosphatidylserine (PS), and this increase in TGF-beta1 protected HK-2 cells against hydrogen peroxide-mediated necrosis. In this study, we aimed to determine whether the sevoflurane-mediated phosphorylation of ERK and Akt, induction of HSP70, and reduction in NF-kappaB activation are due to TGF-beta1 receptor-mediated signaling after PS externalization in HK-2 cells. Exogenous TGF-beta1 and a liposome mixture containing PS mimicked sevoflurane-mediated ERK and Akt phosphorylation and HSP70 induction in HK-2 cells. Sevoflurane and TGF-beta1 caused the nuclear translocation of the SMAD3 transcription factor in HK-2 cells. Furthermore, a neutralizing TGF-beta1 antibody or exogenous annexin V to bind PS prevented sevoflurane-induced ERK and Akt phosphorylation and HSP70 induction in HK-2 cells. Finally, a TGF-beta1 antibody and annexin V attenuated the reduction in nuclear translocation of NF-kappaB by sevoflurane. Therefore, we demonstrate in this study that sevoflurane-mediated cytoprotective and anti-inflammatory effects in HK-2 cells are at least partially due to the externalization of PS and activation of TGF-beta1 signaling pathways.
...
PMID:Sevoflurane-mediated TGF-beta1 signaling in renal proximal tubule cells. 1805 87

We have shown that mouse proximal tubule cells (TKPTS) survive H(2)O(2) stress by activating the cAMP-responsive element binding protein (CREB)-mediated transcription via the canonical EGFR-Ras/ERK pathway. By contrast, cisplatin activates EGFR/Ras/ERK signaling in TKPTS cells yet promotes cell death rather than survival. We now demonstrate that the cisplatin-induced activated EGFR/Ras/ERK signaling cascade fails to activate CREB-mediated transcription even in the presence of phosphorylated CREB. CREB-mediated transcription as well as survival was restored by the histone deacetylase (HDAC) inhibitor trichostatine A (TSA), an effective chemotherapeutic agent. Similar to severe oxidant stress, TSA-mediated survival could be abrogated by inhibition of CREB-mediated transcription. These studies confirm the importance of CREB-mediated transcription in the survival of renal cells subjected to either oxidant- or cisplatin-induced stress. The use of cisplatin and TSA in combined chemotherapy protocols may be an effective strategy to enhance cancer cell death and limit nephrotoxicity.
...
PMID:Restoration of CREB function ameliorates cisplatin cytotoxicity in renal tubular cells. 1809 30

The fully executed epidermal growth factor receptor (EGFR)/Ras/MEK/ERK pathway serves a pro-survival role in renal epithelia under moderate oxidative stress. We and others have demonstrated that during severe oxidative stress, however, the activated EGFR is disconnected from ERK activation in cultured renal proximal tubule cells and also in renal proximal tubules after ischemia/reperfusion injury, resulting in necrotic death. Studies have shown that the tyrosine-phosphorylated p46/52 isoforms of the ShcA family of adaptor proteins connect the activated EGFR to activation of Ras and ERK, whereas the p66(shc) isoform can inhibit this p46/52(shc) function. Here, we determined that severe oxidative stress (after a brief period of activation) terminates activation of the Ras/MEK/ERK pathway, which coincides with ERK/JNK-dependent Ser(36) phosphorylation of p66(shc). Isoform-specific knockdown of p66(shc) or mutation of Ser(36) to Ala, but not to Asp, attenuated severe oxidative stress-mediated ERK inhibition and cell death in vitro. Also, severe oxidative stress (unlike ligand stimulation and moderate oxidative stress, both of which support survival) increased binding of p66(shc) to the activated EGFR and Grb2. This binding dissociated the SOS1 adaptor protein from the EGFR-recruited signaling complex, leading to termination of Ras/MEK/ERK activation. Notably, Ser(36) phosphorylation of p66(shc) and its increased binding to the EGFR also occurred in the kidney after ischemia/reperfusion injury in vivo. At the same time, SOS1 binding to the EGFR declined, similar to the in vitro findings. Thus, the mechanism we propose in vitro offers a means to ameliorate oxidative stress-induced cell injury by either inhibiting Ser(36) phosphorylation of p66(shc) or knocking down p66(shc) expression in vivo.
...
PMID:p66shc inhibits pro-survival epidermal growth factor receptor/ERK signaling during severe oxidative stress in mouse renal proximal tubule cells. 1817 62

The aminoglycoside antibiotic gentamicin elicits proximal tubular toxicity and cell death. In calcium-sensing receptor (CaR)-transfected HEK-293 (CaR-HEK) cells and CaR-expressing proximal tubule-derived opossum kidney (OK) cells, chronic gentamicin treatment elicits dose-dependent, caspase-mediated apoptotic cell death. Here we investigated whether the renal cell toxicity of the CaR agonist gentamicin could be prevented by CaR antagonism or by lithium cotreatment which may interfere with receptor-mediated signalling. Chronic treatment of OK and CaR-HEK cells with low concentrations of gentamicin elicited cell death, an effect that was ameliorated by cotreatment with the CaR negative allosteric modulator (calcilytic) NPS-89636. This calcilytic also attenuated CaR agonist-induced ERK activation in these cells. In addition, 1 mM LiCl, equivalent to its therapeutic plasma concentration, also inhibited gentamicin-induced toxicity in both cell types. This protective effect of lithium was not due to the disruption of phosphatidylinositol-mediated gentamicin uptake as the cellular entry of Texas red-conjugated gentamicin into OK and CaR-HEK cells was unchanged by lithium treatment. However, the protective effect of lithium was mimicked by glycogen synthase 3beta inhibition. Together, these data implicate CaR activation and a lithium-inhibitable signalling pathway in the induction of cell death by gentamicin in renal epithelial cells in culture.
...
PMID:Calcium-sensing receptor antagonism or lithium treatment ameliorates aminoglycoside-induced cell death in renal epithelial cells. 1826 71

We have previously shown that trophic factor supplementation (TFS) of University of Wisconsin (UW) solution reduced early apoptotic changes in vascular endothelial cells. Here, we examine the effect of TFS on cell signaling pathways related to cell growth, differentiation, and apoptosis after cold ischemic storage. In this study, the effect of TFS on the phosphorylation of signaling molecules ERK (extracellular regulated-signaling kinase) 1/2 and p38 MAPK (mitogen activated protein kinases) and of HO-1 (hemeoxygenase-1), relative to changes seen in unmodified UW solution, were determined by Western blot in cells stored under cold ischemic conditions. Primary cultures of canine kidney proximal tubule cells (CKPTC) and human umbilical vein endothelial cells (HUVEC) were used in this study. There was a significant decrease, relative to UW solution, after 1 min rewarming in ERK 1 and 2 activity in CKPTCs. For p38 MAPK, a significant decrease after 5 min rewarming was seen in CKPTC (p<0.05) while significant reductions relative to UW solution were seen in HUVECs after both 1 and 5 min rewarming (p<0.05). Phosphorylated HO-1 was also decreased by 43% and 50% in HUVECs, relative to UW solution, after 1 and 5 min rewarming (p<0.05 at each time point). Collectively, TFS not only limits ERK 1/2 and p38 MAPK activity induced by cold ischemic injury and subsequent rewarming, but also substantially restricted increases in HO-1 phosphorylation.
...
PMID:Prevention of cold ischemia/rewarming-induced ERK 1/2, p38 kinase and HO-1 activation by trophic factor supplementation of UW solution. 1853 57


<< Previous 1 2 3 4 5 6 7 8 9 Next >>

---