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

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Query: UNIPROT:P05412 (c-Jun)
11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endothelins (ET) are powerful effector agents that control multiple aspects of kidney function. This review will focus on endothelin's effect on proximal tubule H+ secretion. The proximal tubule is responsible for reabsorbing approximately 80% of filtered NaHCO3 by a mechanism mediated by H+ secretion. The major fraction (60-70%) of proximal tubule H+ secretion across the apical membrane is mediated by an amiloride inhibitable Na+/H+ antiporter, while the remaining is mediated by a vaculoar H(+)-ATPase. Molecular, immunocytochemical, and inhibitor sensitivity studies all demonstrate that virtually all proximal tubule apical Na+/H+ activity is mediated by NHE3. Hence, regulation of proximal tubule H+ secretion involves, in most cases, regulation of apical membrane NHE3. We have recently shown that stimulation of NHE3 activity in metabolic acidosis is mediated by endothelin-1 (ET-1) working through the endothelin B (ETB) receptor. ET-1/ETB stimulated antiporter activity is due to an increase in apical membrane NHE3 abundance, achieved by an increase in exocytic insertion of NHE3 into the apical membrane. We have also shown that acid-stimulated NHE3 activity depends on activation of Pyk2, c-Src, MAP kinase, and the immediate early genes c-Fos and c-Jun. This article summarizes these findings and proposes an acid-activated signaling pathway that is responsible for the increase in NHE3 activity in metabolic acidosis.
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PMID:The role of endothelin in proximal tubule proton secretion and the adaptation to a chronic metabolic acidosis. 1202 24

Both integrin-based focal adhesion complexes and receptor tyrosine kinases have been proposed as scaffolds on which the G protein-coupled receptor (GPCR)-induced signaling complex might assemble. We have recently reported that Ca2+-sensitive tyrosine kinase, Pyk2, and epidermal growth factor receptor (EGFR) act as independently regulated scaffolds in cardiomyocytes. In this report, we investigated the activation and regulation of p130Cas, Crk, Pyk2, and c-Src by a well-known hypertrophic agonist, endothelin-1 (ET), and determined their contributions to the activation of c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) in cardiomyocytes. Like Pyk2, ET-induced tyrosine phosphorylation of p130Cas was significantly inhibited by either chelating intracellular Ca2+ ([Ca2+]i) or a protein kinase C inhibitor, calphostin C. This activation of p130Cas was also abrogated by the tetrapeptide RGDS, which disrupts integrin heterodimerization; cytochalasin D, which depolymerizes the actin cytoskeleton; or a selective Src family kinase inhibitor, PP2, but not by an EGFR inhibitor, AG1478. We also observed ET-induced temporal associations of Pyk2 with active c-Src, followed by p130Cas with Pyk2, c-Src, and Crk. Overexpression of a dominant-negative mutant of p130Cas (CasDeltaSD), Crk (CrkSH2m), Pyk2 (PKM), or C-terminal Src kinase (Csk), but not of a deletion mutant of EGFR (533delEGFR), attenuated ET-induced JNK activation. Similarly, an ET-induced increase in c-jun promoter luciferase activity was inhibited by overexpression of CasDeltaSD, CrkSH2m, PKM, or Csk. In contrast, ET-induced ERK activation and c-fos gene expression were predominantly regulated by EGFR. Collectively, the focal adhesion-dependent p130Cas/Crk/Pyk2/c-Src-mediated pathway is selectively involved in ET-induced JNK activation in cardiomyocytes.
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PMID:Selective involvement of p130Cas/Crk/Pyk2/c-Src in endothelin-1-induced JNK activation. 1271 47

The role of src-family tyrosine kinases in LPS-induced DC maturation has not been fully addressed. We show that LPS induces activation of c-Src and Lyn in human DC. Inhibition of these kinasesby PP1 uncoupled LPS-induced cytokine production from the up-regulation of costimulatory molecules, resulting in DC still capable of stimulating T cell proliferation but much less efficient in inducing Th1 differentiation. This is the first example of a pharmacological inhibitor able to modulate the capacity of DC to induce a particular type of immune response. Inhibition of src-family kinases impaired phosphorylation and accumulation of c-Jun, leading to reduced formation of AP-1 complexes upon LPS stimulation. Thus, src-kinases control cytokine production in LPS-induced DC maturation through a timely formation of AP-1.
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PMID:Activation of src-family tyrosine kinases by LPS regulates cytokine production in dendritic cells by controlling AP-1 formation. 1451 67

A standard therapy used today for prostate cancer is androgen ablation by gonadotropin-releasing hormone analogs (GnRH-a). Although most patients respond to androgen ablation as an initial systemic therapy, nearly all cases will develop androgen resistance, the management of which is still a major challenge. Here, we report that GnRH-a can directly induce apoptosis of the androgen-independent prostate cancer-derived DU145 and PC3 cell lines. Using specific inhibitors, we found that the apoptotic effect of GnRH-a is mediated by c-Jun NH2-terminal kinase (JNK) and inhibited by the phosphatidylinositol 3'-kinase (PI3K)-protein kinase B (PKB) pathway. Indeed, in DU145 cells, GnRH-a activates the JNK cascade in a c-Src- and MLK3-dependent manner but does not involve protein kinase C and epidermal growth factor receptor. Concomitantly, GnRH-a reduces the activity of the PI3K-PKB pathway, which results in the dephosphorylation of PKB mainly in the nucleus. The reduction of PKB activity releases PKB-induced inhibition of MLK3 and thus further stimulates JNK activity and accelerates the apoptotic effect of GnRH-a. Interestingly, extracellular signal-regulated kinase is also activated by GnRH-a, and this occurs via a pathway that involves matrix metalloproteinases and epidermal growth factor receptor, but its activation does not affect JNK activation and the GnRH-a-induced apoptosis. Our results support a potential use of GnRH-a for the treatment of advanced prostate cancer and suggest that the outcome of this treatment can be amplified by using PI3K-PKB inhibitors.
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PMID:Gonadotropin-releasing hormone induces apoptosis of prostate cancer cells: role of c-Jun NH2-terminal kinase, protein kinase B, and extracellular signal-regulated kinase pathways. 1531 14

The importance of prolactin (PRL) in physiological proliferation and differentiation of the mammary gland, together with high levels of PRL receptors in breast tumors, the association of circulating PRL with incidence of breast cancer, and the recognition of locally produced PRL, point to the need for greater understanding of PRL actions in mammary disease. Although PRL has been shown to activate multiple kinase cascades in various target cells, relatively little is known of its signaling pathways in the mammary gland apart from the Janus kinase 2/ signal transducer and activator of transcription 5 pathway, particularly in tumor cells. Another potential effector is activating protein-1 (AP-1), a transcription complex that regulates processes essential for neoplastic progression, including proliferation, survival and invasion. We demonstrate that PRL activates AP-1 in MCF-7 cells, detectable at 4 h and sustained for at least 24 h. Although Janus kinase 2 and ERK1/2 are the primary mediators of PRL-induced signals, c-Src, phosphatidylinositol 3'-kinase, protein kinase C, and other MAPKs contribute to maximal activity. PRL activation of these pathways leads to increased c-Jun protein and phosphorylation, JunB protein, and phosphorylation of c-Fos, elevating the levels of AP-1 complexes able to bind DNA. These active AP-1 dimers may direct expression of multiple target genes, mediating some of PRL's actions in mammary disease.
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PMID:Multiple kinase cascades mediate prolactin signals to activating protein-1 in breast cancer cells. 1531 52

We previously demonstrated that low K intake stimulated the expression of c-Src and that stimulation of protein tyrosine kinase inhibited ROMK channel activity (Wei, Y., Bloom, P., Lin, D. H., Gu, R. M., and Wang, W. H. (2001) Am. J. Physiol. 281, F206-F212). Decreases in dietary K content significantly increased O(2)(-) levels and the phosphorylation of c-Jun, a transcription factor, in renal cortex and outer medulla. The role of O(2)(-) and related products such as H(2)O(2) in stimulating the expression of protein tyrosine kinase is suggested by the observation that addition of 50-200 microm H(2)O(2) increased the phosphorylation of c-Jun and the expression of c-Src in M1 cells, a mouse collecting duct principal cell line. The effect of H(2)O(2) on c-Src expression was completely abolished with cyclohexamide or actinomycin D. The treatment of animals on a K-deficient (KD) diet with tempol for 7 days significantly decreased the production of O(2)(-), c-Jun phosphorylation, and c-Src expression. Moreover, low K intake decreased the activity of ROMK-like small conductance channels from 1.37 (control K diet) to 0.5 in the cortical collecting duct and increased the tyrosine phosphorylation of ROMK in the renal cortex and outer medulla. In contrast, the tempol treatment not only increased channel activity to 1.1 in the cortical collecting duct but also decreased the tyrosine phosphorylation of ROMK from rats on a KD diet. Finally, suppressing O(2)(-) production with tempol significantly increased renal K excretion measured with metabolic cage and lowered the plasma K concentration in comparison with those on a KD diet alone without tempol. We conclude that O(2)(-) and related products play a role in mediating the effect of low K intake on c-Src expression and in suppressing ROMK channel activity and renal K secretion.
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PMID:Superoxide anions are involved in mediating the effect of low K intake on c-Src expression and renal K secretion in the cortical collecting duct. 1564 19

We recently demonstrated that the chemokine CXCL16 is expressed in aortic smooth muscle cells (ASMC) and induces ASMC adhesion and proliferation (Chandrasekar, B., Bysani, S., and Mummidi, S. (2004) J. Biol. Chem. 279, 3188-3196). Here we reort that interleukin (IL)-18 positively regulates CXCL16 transcription in rat ASMC. We characterized the cis-regulatory region of CXCL16 and identified a functional activator protein-1 (AP-1) binding motif. Deletion or mutation of this site attenuated IL-18-mediated CXCL16 promoter activity. Gel shift, supershift, and chromatin immunoprecipitation assays confirmed AP-1-dependent CXCL16 expression. CXCL16 promoter-reporter activity was increased by constitutively active c-Fos and c-Jun and decreased by dominant negative or antisense c-Fos and c-Jun. Src kinase inhibitors PP1 and PP2, phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and LY294002, Akt inhibitor, the c-Jun N-terminal kinase (JNK) inhibitor SP600125, antisense JNK and dominant negative MyD88, interleukin-1 receptor-associated kinase (IRAK)-1, IRAK4, and phosphatidylinositol 3-kinase expression all attenuated IL-18-mediated AP-1 binding and reporter activity, CXCL16 promoter-reporter activity, and CXCL16 expression. Thus IL-18 induced CXCL16 expression via a MyD88 --> IRAK1-IRAK4-TRAF6 (tumor necrosis factor receptor-associated factor 6) --> c-Src--> PI3K --> Akt --> JNK --> AP-1 pathway. Importantly, IL-18 stimulated ASMC proliferation in a CXCL16-dependent manner. These data provide for the first time a mechanism of IL-18-mediated CXCL16 gene transcription and CXCL16-dependent ASMC proliferation and suggest a role for IL-18-CXCL16 cross-talk in atherogenesis and restenosis following angioplasty.
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PMID:The pro-atherogenic cytokine interleukin-18 induces CXCL16 expression in rat aortic smooth muscle cells via MyD88, interleukin-1 receptor-associated kinase, tumor necrosis factor receptor-associated factor 6, c-Src, phosphatidylinositol 3-kinase, Akt, c-Jun N-terminal kinase, and activator protein-1 signaling. 1589 Jun 43

CD95 ligand (CD95L) triggers a rapid formation of reactive oxygen species (ROS) as an upstream event of CD95 activation and apoptosis induction in rat hepatocytes. This ROS response was sensitive to inhibition by diphenyleneiodonium, apocynin, and neopterin, suggestive of an involvement of NADPH oxidases. In line with this, hepatocytes expressed mRNAs not only of the phagocyte gp91phox (Nox 2), but also of the homologs Nox 1 and 4 and Duox 1 and 2, as well as the regulatory subunit p47phox. gp91phox (Nox 2) and p47phox were also identified at the protein level in rat hepatocytes. CD95L induced within 1 min ceramide formation and serine phosphorylation of p47phox, which was sensitive to inhibitors of sphingomyelinase and protein kinase Czeta (PKCzeta). These inhibitors and p47phox protein knockdown inhibited the early CD95L-induced ROS response, suggesting that ceramide and PKCzeta are upstream events of the CD95L-induced Nox/Duox activation. CD95L also induced rapid activation of the Src family kinase Yes, being followed by activation of c-Src, Fyn, and c-Jun-N-terminal kinases (JNK). Only Yes and JNK activation were sensitive to N-acetylcysteine, inhibitors of NADPH oxidase, PKCzeta, or sphingomyelinase, indicating that the CD95L-induced ROS response is upstream of Yes and JNK but not of Fyn and c-Src activation. Activated Yes rapidly associated with the epidermal growth factor receptor (EGFR), which became phosphorylated at Tyr845 and Tyr1173 but not at Tyr1045. Activated EGFR then triggered an AG1478-sensitive CD95-tyrosine phosphorylation, which was a signal for membrane targeting of the EGFR/CD95 complex, subsequent recruitment of Fas-associated death domain and caspase 8, and apoptosis induction. All of these events were significantly blunted by inhibitors of sphingomyelinase, PKCzeta, NADPH oxidases, Yes, or EGFR-tyrosine kinase activity and after protein knockdown of either p47phox, Yes, or EGFR. The data suggest that CD95L-induced apoptosis involves a sphingomyelinase- and PKCzeta-dependent activation of NADPH oxidase isoforms, which is required for Yes/EGFR/CD95 interactions as upstream events of CD95 activation.
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PMID:Involvement of NADPH oxidase isoforms and Src family kinases in CD95-dependent hepatocyte apoptosis. 1591 50

Protein tyrosine kinases (PTKs) and mitogen-activated protein kinases (MAPKs) have been demonstrated to play a crucial role in the signaling pathways induced by silica. In the present study, we investigated whether Src family TKs play a role in crystalline silica-induced NF-kappaB activation and whether NF-kappaB activation requires Src TK-dependent MAPK activity in RAW 264.7 cells, a mouse peritoneal macrophage cell line. Selective Src TK inhibitors, damnacanthal or PP1, inhibited silica-induced NF-kappaB activation in a dose-dependent manner. Furthermore, these kinase inhibitors suppressed silica-induced tyrosine phosphorylation of IkappaB-alpha and p65 NF-kappaB. Within a similar time frame, c-Src and Lck were physically associated with IkappaB-alpha and with p65 NF-kappaB. Silica stimulated the phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), but not p38 MAPK and c-Jun NH(2)-terminal kinase 1 and 2 (JNK1/2). Damnacanthal or PP1 substantially blocked the silica-induced activation of ERK1/2. Moreover, PD98059, an inhibitor of ERK1/2, or SB203580, an inhibitor of p38 MAPK, failed to inhibit silica-induced NF-kappaB activation. These results suggest that c-Src and Lck act for silica-induced NF-kappaB activation by mediating the tyrosine phosphorylations of IkappaB-alpha and p65 NF-kappaB. However, the Src TK-dependent activation of ERK1/2 may not be involved in the silica signaling pathway leading to NF-kappaB activation.
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PMID:Src tyrosine kinases mediate crystalline silica-induced NF-kappaB activation through tyrosine phosphorylation of IkappaB-alpha and p65 NF-kappaB in RAW 264.7 macrophages. 1643 47

Hematopoietic restrictive Galpha(16) has long been known to stimulate phospholipase Cbeta (PLCbeta) and induce mitogen-activated protein kinase (MAPK) phosphorylation. Recently, we have demonstrated that Galpha(16) is capable of inducing the phosphorylation and transcriptional activation of transcription factors, such as signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappaB (NFkappaB). However, the downstream signaling regulation by Galpha(16) has not yet been documented. In the present study, we have determined the signaling mechanism by which constitutively active Galpha(16) mediates c-Fos transcriptional activation in human embryonic kidney (HEK) 293 cells. Overexpression of constitutively active Galpha(16), Galpha(16)QL, resulted in the stimulation of c-Fos transcriptional activation in HEK 293 cells. The participation of PLCbeta, c-Src/Janus kinase 2 (JAK2) and extracellular signal-regulated kinase (ERK) signaling pathways in Galpha(16)QL-induced c-Fos transcriptional activation was demonstrated by the use of their specific inhibitors. However, c-Jun N terminal kinase (JNK), p38 MAPK and phosphatidylinositol-3 kinase (PI3K) were not required. Interestingly, the dominant negative mutant of STAT1, but not STAT3, suppressed c-Fos transcriptional activation induced by Galpha(16)QL, implying that STAT1 was involved in this signaling mechanism. To further examine the role of STAT1 in the signaling pathway of Galpha(16), we demonstrated that Galpha(16)QL was able to induce STAT1 activation. Also, stimulation of adenosine A1 receptor-coupled Galpha(16) was shown to induce ERK and STAT1 phosphorylations in a concentration-dependent manner. Using selective inhibitors, PLCbeta, c-Src/JAK and ERK, but not JNK, p38 MAPK and PI3K, were shown to be involved in Galpha(16)QL-induced STAT1 activation. Collectively, our results demonstrate for the first time that stimulation of Galpha(16) can lead to STAT1-dependent c-Fos transcriptional activation via PLCbeta, c-Src/JAK and ERK pathways.
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PMID:Transcriptional activation of c-Fos by constitutively active Galpha(16)QL through a STAT1-dependent pathway. 1678 47


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