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)

Rac1, a Rho family GTPase, is a mediator of diverse cellular functions including membrane ruffling, cell cycle progression, and transformation. Rac3, a close relative of Rac1, is less well characterized. Posttranslational addition of geranylgeranyl isoprenoid lipids to Rac proteins is required for biological activity. Inhibitors of geranylgeranyl transferase I (GGTIs) are currently under investigation as a possible anticancer therapy, although the targets of GGTIs have not been determined. We created COOH-terminal mutants of Rac1 and Rac3 that are farnesylated and used them to characterize Rac1 and Rac3 as physiological targets of GGTIs. We show that, like Rac1, activated Rac3 causes transformation and leads to membrane ruffling. Farnesylated versions of Rac1 and Rac3 retain the ability to signal to the transcription factor c-Jun and cause membrane ruffling and transformation, indicating that switching isoprenoid modification does not alter function. Finally, treatment with GGTIs led to the inhibition of membrane-ruffling and transforming activities of both activated and wild-type Rac1 and Rac3. However, the farnesylated versions of both activated and wild-type Rac1 and Rac3 were resistant to the inhibitory effects of GGTIs. These results illustrate that Rac1 and Rac3 are potential physiological targets for these novel drugs.
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PMID:Rac1 and Rac3 are targets for geranylgeranyltransferase I inhibitor-mediated inhibition of signaling, transformation, and membrane ruffling. 1463 27

Yersinia enterocolitica triggers activation of the nuclear factor (NF)-kappaB and production of the proinflammatory chemokine interleukin (IL)-8 in intestinal epithelial cells. This activation is due to adhesion of the bacteria via their outer membrane protein invasin to the host cells. Using Clostridium difficile toxins that specifically inactivate small GTPases, and transfection of inhibitory proteins of the Rho-GTPases, we demonstrate that Rac1, but not Cdc42 or Rho, is required for activation of NF-kappaB by invasin. Invasin activated the mitogen activated protein kinases (MAPK) p38 and c-Jun N-terminal protein kinase (JNK) but not extracellular signal regulated kinase (ERK). The functional relevance of these pathways for invasin-mediated IL-8 expression was assessed by protein kinase inhibitors and dominant-negative kinase mutants. While NF-kappaB and JNK contribute to IL-8 transcription, p38 MAPK also acts through stabilization of IL-8 mRNA, as confirmed by quantitative RT-PCR and electrophoretic mobility shift assays. Transfection experiments with I-kappaB kinase (IKK)1 and IKK2 mutants indicate that the release of NF-kappaB from its cytoplasmic inhibitor I-kappaB and its translocation into the nucleus is mediated by these kinases. Our data identify Rac1 as a key intermediate in invasin-triggered IL-8 synthesis and demonstrate that maximum IL-8 induction involves several MAP kinase cascades.
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PMID:Activation of NF-kappaB and IL-8 by Yersinia enterocolitica invasin protein is conferred by engagement of Rac1 and MAP kinase cascades. 1464 Nov 80

The beta and gamma subunits of heterotrimeric GTP-binding proteins (Gbetagamma) were found to bi-directionally regulate the UV-induced activation of p38 and c-Jun NH(2)-terminal kinase, and the UV-induced activation of p38 was reported to enhance the resistance of normal keratinocytes to apoptosis. However, the signaling pathway downstream of Gbetagamma for this UV-induced p38 activation is not known. Thus, we examined the role of the Rho GTPase family in the regulation of UV-induced p38 activation by Gbetagamma. We found that overexpression of Gbetagamma increased the UV-induced activation of Cdc42 and that overexpression of constitutively active V12 Cdc42 increased the UV-induced p38 activation. Transfection of dominant negative N17 Cdc42 or small interfering RNA for Cdc42 blocked UV-induced p38 activation mediated by Gbetagamma in COS-1 and HaCaT cells. UV-induced p38 activation by Gbetagamma was blocked by overexpression of dominant negative p21-activated kinase (PAK)-interacting exchange factor beta (betaPix), and wild type betaPix stimulated the UV-induced p38 activation, which was blocked by N17 Cdc42. Gbetagamma increased the UV-induced activation of Ras, and the overexpression of V12 Ras increased UV-induced p38 activation, which was blocked by dominant negative betaPix. UV-induced p38 activation was inhibited by N17 Ras and a farnesyltransferase inhibitor, manumycin A. Gbetagamma also increased the UV-induced phosphorylation of the epidermal growth factor receptor (EGFR), and the UV-induced p38 activation was blocked by an EGFR kinase inhibitor, AG1478. From these results, we conclude that Gbetagamma mediates UV-induced activation of p38 in a Cdc42-dependent way and that EGFR, Ras, and betaPix act sequentially upstream of Cdc42 in COS-1 and HaCaT cells.
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PMID:Cdc42-dependent mediation of UV-induced p38 activation by G protein betagamma subunits. 1497 Feb 10

In the present study, we examined signal transduction mechanism of reactive oxygen species (ROS) production and the role of ROS in angiotensin II-induced activation of mitogen-activated protein kinases (MAPKs) in rat neonatal cardiomyocytes. Among three MAPKs, c-Jun NH(2)-terminal kinase (JNK) and p38 MAPK required ROS production for activation, as an NADPH oxidase inhibitor, diphenyleneiodonium, inhibited the activation. The angiotensin II-induced activation of JNK and p38 MAPK was also inhibited by the expression of the Galpha(12/13)-specific regulator of G protein signaling (RGS) domain, a specific inhibitor of Galpha(12/13), but not by an RGS domain specific for Galpha(q). Constitutively active Galpha(12)- or Galpha(13)-induced activation of JNK and p38 MAPK, but not extracellular signal-regulated kinase (ERK), was inhibited by diphenyleneiodonium. Angiotensin II receptor stimulation rapidly activated Galpha(13), which was completely inhibited by the Galpha(12/13)-specific RGS domain. Furthermore, the Galpha(12/13)-specific but not the Galpha(q)-specific RGS domain inhibited angiotensin II-induced ROS production. Dominant negative Rac inhibited angiotensin II-stimulated ROS production, JNK activation, and p38 MAPK activation but did not affect ERK activation. Rac activation was mediated by Rho and Rho kinase, because Rac activation was inhibited by C3 toxin and a Rho kinase inhibitor, Y27632. Furthermore, angiotensin II-induced Rho activation was inhibited by Galpha(12/13)-specific RGS domain but not dominant negative Rac. An inhibitor of epidermal growth factor receptor kinase AG1478 did not affect angiotensin II-induced JNK activation cascade. These results suggest that Galpha(12/13)-mediated ROS production through Rho and Rac is essential for JNK and p38 MAPK activation.
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PMID:G alpha 12/13- and reactive oxygen species-dependent activation of c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase by angiotensin receptor stimulation in rat neonatal cardiomyocytes. 1574 61

Cyclooxygenase 2 (COX-2) is an immediate early gene induced by a variety of stimuli and its expression is stimulated by individual activation of Ras or Rho GTPases. Here we investigate the role of coordinate activation of Ras and Rho GTPases in the induction of COX-2. Individual expression of constitutively active Ras, RhoA, or Rac1 was capable of stimulating COX-2 expression in NIH3T3 cells, but co-expression of constitutively active RhoA with either constitutively active Ras or Rac1 was required for full stimulation of COX-2 expression. Serum growth factors differentially activated Ras, RhoA, and Rac1, which correlated with the activation of Raf-1, ERK, and c-Jun as well as with induction of COX-2. Inhibition of Ras significantly blocked the activation of Raf-1, ERK, and c-Jun and the stimulation of COX-2 expression in response to serum. In contrast, inhibition of Rho family GTPases partially blocked serum induction of ERK activation but had little effects on COX-2 expression. Both inhibitors of MEK (PD098059) and JNK (SP600125) inhibited serum induction of COX-2. PD98059 only inhibited constitutively active Ras-induced COX-2 expression, while SP600125 significantly inhibited both constitutively active Ras- and RhoA-induced COX-2 expression. Together, our data suggest that constitutively active oncogenic Ras and Rho coordinately stimulate COX-2 expression whereas transient activation of Ras but not RhoA or Rac1 mediates the induction of COX-2 in response to serum. Furthermore, ERK and JNK activation are both required for serum- and oncogenic Ras-mediated COX-2 expression whereas only JNK activation is required for oncogenic RhoA-mediated stimulation of COX-2 expression.
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PMID:Differential regulation of cyclooxygenase 2 expression by small GTPases Ras, Rac1, and RhoA. 1608 58

Rho GTPases are key transducers of integrin/extracellular matrix and growth factor signaling. Although integrin-mediated adhesion and trophic support suppress neuronal apoptosis, the role of Rho GTPases in neuronal survival is unclear. Here, we have identified Rac as a critical pro-survival GTPase in cerebellar granule neurons (CGNs) and elucidated a death pathway triggered by its inactivation. GTP-loading of Rac1 was maintained in CGNs by integrin-mediated (RGD-dependent) cell attachment and trophic support. Clostridium difficile toxin B (ToxB), a specific Rho family inhibitor, induced a selective caspase-mediated degradation of Rac1 without affecting RhoA or Cdc42 protein levels. Both ToxB and dominant-negative N17Rac1 elicited CGN apoptosis, characterized by cytochrome c release and activation of caspase-9 and -3, whereas dominant-negative N19RhoA or N17Cdc42 did not cause significant cell death. ToxB stimulated mitochondrial translocation and conformational activation of Bax, c-Jun activation, and induction of the BH3-only protein Bim. Similarly, c-Jun activation and Bim induction were observed with N17Rac1. A c-jun N-terminal protein kinase (JNK)/p38 inhibitor, SB203580, and a JNK-specific inhibitor, SP600125, significantly decreased ToxB-induced Bim expression and blunted each subsequent step of the apoptotic cascade. These results indicate that Rac acts downstream of integrins and growth factors to promote neuronal survival by repressing c-Jun/Bim-mediated mitochondrial apoptosis.
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PMID:Inhibition of Rac GTPase triggers a c-Jun- and Bim-dependent mitochondrial apoptotic cascade in cerebellar granule neurons. 1609 44

Leukocyte transmigration can be affected by shear stress; however, the mechanisms by which shear stress modulates transmigration are unknown. We found that adhesion of eosinophils or an eosinophilic cell line to intereukin 4-stimulated endothelial cells led to a shear-dependent increase in endothelial cell intracellular calcium and increased phosphorylation of extracellular signal-regulated kinase (ERK) 2, but not c-Jun NH2-terminal kinase or p38 mitogen-activated protein kinase. Latex beads coated with antibodies were used to characterize the role of specific endothelial cell surface molecules in initiating signaling under shear conditions. We found that ligation of either vascular cell adhesion molecule-1 or E-selectin, but not major histocompatibility complex class I, induced a shear-dependent increase in ERK2 phosphorylation in cytokine-stimulated endothelial cells. Disassembly of the actin cytoskeleton with latrunculin A prevented ERK2 phosphorylation after adhesion under flow conditions, supporting a role for the cytoskeleton in mechano-sensing. Rapid phosphorylation of focal adhesion kinase and paxillin occurred under identical conditions, suggesting that focal adhesions were also involved in mechanotransduction. Finally, we found that Rho-associated protein kinase and calpain were both critical in the subsequent transendothelial migration of eosinophils under flow conditions. These data suggest that ligation of leukocyte adhesion molecules under flow conditions leads to mechanotransduction in endothelial cells, which can regulate subsequent leukocyte trafficking.
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PMID:Eosinophil adhesion under flow conditions activates mechanosensitive signaling pathways in human endothelial cells. 1617 63

Streptococcus pneumoniae is the major pathogen of community-acquired pneumonia. The respiratory epithelium constitutes the first line of defense against invading lung pathogens, including pneumococci. We analyzed the involvement of Toll-like receptors (TLR) and Rho-GTPase signaling in the activation of human lung epithelial cells by pneumococci. S. pneumoniae induced release of interleukin-8 (IL-8) by human bronchial epithelial cell line BEAS-2B. Specific inhibition of Rac1 by Nsc23766 or a dominant-negative mutant of Rac1 strongly reduced cytokine release. In addition, pneumococci-related cell activation (IL-8 release, NF-kappaB-activation) depended on MyD88, phosphatidylinositol 3-kinase, and Cdc42 but not on RhoA. Pneumococci enhanced TLR1 and TLR2 mRNA expression in BEAS-2B cells, whereas TLR4 and TLR6 expression was constitutively high. TLR1 and 2 synergistically recognized pneumococci in cotransfection experiments. TLR4, TLR6, LPS-binding protein, and CD14 seem not to be involved in pneumococci-dependent cell activation. At the IL-8 gene promoter, recruitment of phosphorylated NF-kappaB subunit p65 was blocked by inhibition of Rac1, whereas binding of the phosphorylated activator protein-1 subunit c-Jun to the promoter was not diminished. In summary, these results suggest that S. pneumoniae activate human epithelial cells by TLR1/2 and a phosphatidylinositol 3-kinase- and Rac1-dependent NF-kappaB-recruitment to the IL-8 promoter.
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PMID:Pneumococci induced TLR- and Rac1-dependent NF-kappaB-recruitment to the IL-8 promoter in lung epithelial cells. 1629 55

Tumour angiogenesis is mediated by increased levels of vascular endothelial growth factor (VEGF). We have studied the mechanism by which endogenous activation of Rho oncoproteins regulates VEGF expression in COS-7 and NIH3T3 cells. We carried out transient and stable transfection with constitutively activated rhoA, rac1, and cdc42 mutants in COS-7 and NIH3T3 cells, respectively in the absence of external stimuli. Western blot and inmunohistochemistry assays of those cells revealed increased VEGF protein expression. Cotransfection with constitutively activated rhoA, rac1, and cdc42 mutants and a VEGF promoter-reporter construct showed an increase in VEGF promoter transcriptional activity induced by Rho oncoproteins in COS-7 and NIH3T3. c-Jun kinase had been described as a MAPK involved in Rho oncoproteins pathways. Interestingly, we found that c-Jun kinase chemical inhibition as well as transient transactivation assays using dominant negative c-Jun kinase mutant abolished the VEGF promoter transcriptional induction by Rac1 and Cdc42 but not by RhoA. These findings indicate that Rho oncoprotein endogenously activated regulates VEGF expression through a transcriptional mechanism, and that the c-Jun kinase activity is a mediator in the expression of VEGF induced by Rac1 and Cdc42 oncoproteins, but not of that induced by RhoA.
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PMID:c-Jun kinase mediates expression of VEGF induced at transcriptional level by Rac1 and Cdc42Hs but not by RhoA. 1644 Mar 8

The transcription factor AP-1, which is composed of Fos and Jun family proteins, plays an essential role in tumor cell invasion by altering gene expression. We report here that Krp1, the AP-1 up-regulated protein that has a role in pseudopodial elongation in v-Fos-transformed rat fibroblast cells, forms a novel interaction with the nondifferentially expressed actin binding protein Lasp-1. Krp1 and Lasp-1 colocalize with actin at the tips of pseudopodia, and this localization is maintained by continued AP-1 mediated down-regulation of fibronectin that in turn suppresses integrin and Rho-ROCK signaling and allows pseudopodial protrusion and mesenchyme-like invasion. Mutation analysis of Lasp-1 demonstrates that its SH3 domain is necessary for pseudopodial extension and invasion. The results support the concept of an AP-1-regulated multigenic invasion program in which proteins encoded by differentially expressed genes direct the function, localization, and activity of proteins that are not differentially expressed to enhance the invasiveness of cells.
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PMID:AP-1 differentially expressed proteins Krp1 and fibronectin cooperatively enhance Rho-ROCK-independent mesenchymal invasion by altering the function, localization, and activity of nondifferentially expressed proteins. 1644 58


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