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 c-Abl protein tyrosine kinase is activated by certain DNA-damaging agents and regulates induction of the stress-activated c-Jun N-terminal protein kinase (SAPK). Here we show that nuclear c-Abl associates with MEK kinase 1 (MEKK-1), an upstream effector of the SEK1-->SAPK pathway, in the response of cells to genotoxic stress. The results demonstrate that the nuclear c-Abl binds to MEKK-1 and that c-Abl phosphorylates MEKK-1 in vitro and in vivo. Transient-transfection studies with wild-type and kinase-inactive c-Abl demonstrate c-Abl kinase-dependent activation of MEKK-1. Moreover, c-Abl activates MEKK-1 in vitro and in response to DNA damage. The results also demonstrate that c-Abl induces MEKK-1-mediated phosphorylation and activation of SEK1-SAPK in coupled kinase assays. These findings indicate that c-Abl functions upstream of MEKK-1-dependent activation of SAPK in the response to genotoxic stress.
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PMID:Activation of MEK kinase 1 by the c-Abl protein tyrosine kinase in response to DNA damage. 1086 55

Extracellular matrix facilitates anchorage-dependent cell survival via interaction of its arginine-glycine-aspartate (RGD) motif with integrins. In this report, we describe an unexpected, apoptosis-promoting the effect of immobilized RGD (iRGD) on tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis. Mesangial cells cultured on RGD-coated plates showed enhanced susceptibility to TNF-alpha-induced apoptosis. iRGD alone did not affect cell survival. In contrast, iRGD did not facilitate but inhibited apoptosis induced by H(2)O(2). Mitogen-activated protein (MAP) kinases and tyrosine kinases are important mediators for the RGD-integrin signaling. Pretreatment with MAP kinase kinase inhibitor PD098059, c-Jun N-terminal kinase (JNK)-c-Jun/AP-1 inhibitor curcumin or p38 MAP kinase inhibitor SB203580 did not attenuate the apoptosis-promoting effect of iRGD. Consistently, transfection with dominant-negative mutants of extracellular signal-regulated kinases, JNK or p38 MAP kinase did not inhibit the effect of iRGD. In contrast, protein tyrosine kinase inhibitors, genistein, and herbimycin A, abrogated the apoptosis-promoting effect of iRGD. Of note, TNF-alpha-induced apoptosis on uncoated plates was not attenuated by tyrosine kinase inhibitors. These data provide the first evidence that iRGD accelerates certain apoptosis. We identified that the effect was mediated by the tyrosine kinase-dependent, MAP kinase-independent mechanism.
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PMID:Enhancement of TNF-alpha-induced apoptosis by immobilized arginine-glycine-aspartate: involvement of a tyrosine kinase-dependent, MAP kinase-independent mechanism. 1103 20

Because of its dual roles in acute toxicity and in therapeutic application in cancer treatment, arsenic has recently attracted a renewed attention. In this study, we report NaAsO(2)-induced signal cascades from the cell surface to the nucleus of murine thymic T lymphocytes that involve membrane rafts as an initial signal transducer. NaAsO(2) induced apoptosis through fragmentation of DNA, activation of caspase, and reciprocal regulation of Bcl-2/Bax with the concomitant reduction of membrane potential. We demonstrated that NaAsO(2)-induced caspase activation is dependent on curcumin-sensitive c-Jun amino-terminal kinase and barely dependent on SB203580-sensitive p38 kinase or PD98059-sensitive extracellular signal-regulated kinase. Additionally, staurosporine, which severely inhibited the activation of mitogen-activated protein (MAP) family kinases and c-Jun, partially blocked the NaAsO(2)-mediated signal for poly(ADP-ribose) polymerase (PARP) degradation. Potentially as the initial cell surface event for intracellular signaling, NaAsO(2) induced aggregation of GPI-anchored protein Thy-1 and superoxide production. This Thy-1 aggregation and subsequent activation of MAP family kinase and c-Jun and the degradation of PARP induced by NaAsO(2) were all inhibited by DTT, suggesting the requirement of interaction between arsenic and protein sulfhydryl groups for those effects. beta cyclodextrin, which sequestrates cholesterol from the membrane rafts, inhibited NaAsO(2)-induced activation of protein tyrosine kinases and MAP family kinases, degradation of PARP, and production of superoxide. In addition, beta cyclodextrin dispersed NaAsO(2)-induced Thy-1 clustering. These results suggest that a membrane raft integrity-dependent cell surface event is a prerequisite for NaAsO(2)-induced protein tyrosine kinase/c-Jun amino-terminal kinase activation, superoxide production, and downstream caspase activation.
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PMID:Arsenite induces apoptosis of murine T lymphocytes through membrane raft-linked signaling for activation of c-Jun amino-terminal kinase. 1103 63

In our previous studies, we showed that angelan, a polysaccharide purified from Angelica gigas Nakai, specifically activated macrophages to induce cytokines including inducible nitric oxide synthase (iNOS) which has strong anti-tumor activities [Immunopharmacology, 1999; 43: 1.]. In the present study, we investigated the intracellular signal transduction pathways involved in the angelan-induced iNOS synthesis by murine macrophages. Protein tyrosine phosphorylation was induced within 5 min by angelan, and the blocking of protein tyrosine kinases (PTKs) inhibited down-stream pathways leading to iNOS production in response to angelan. Treament of RAW 264.7 cells with angelan resulted in significant activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and p38, while stress-activated protein kinase/c-Jun NH2 terminal kinase (SAPK/JNK) was not activated by angelan. The specific p38 inhibitor SB203580 abrogated the angelan-induced iNOS synthesis, whereas the selective mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1 (MEK-1) inhibitor PD98059 did not affect the iNOS induction. In conclusion, we demonstrate that PTK and p38 MAPK activation are required to transduce signals leading to iNOS expression in angelan-stimulated murine macrophages.
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PMID:Activation of mitogen-activated protein kinase pathways by angelan in murine macrophages. 1136 Sep 25

B-cell chronic lymphocytic leukemia (B-CLL) cells express on their surface membranes immunoglobulin (Ig) M or IgD, both of which normally function as B-cell antigen receptors (BCRs). However, in contrast to normal B-cells, in B-CLL cells several important signaling pathways, such as the activation of protein tyrosine kinase via BCR, are defective. We have examined whether the activities of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), p38 MAPK, and Akt kinase, are functional in B-CLL cells, because these kinases play critical roles in activation in response to BCR stimulation, tumor cell growth, and survival. In B-CLL cells, BCR cross-linking neither induced activation nor enhanced the activities of Lyn, Syk, p21ras, JNK, p38 MAPK, or Akt kinases, whereas p38 MAPK and Akt were constitutively active. In contrast, BCR cross-linking resulted in ERK activation, although the activation in quiescent cells was case dependent. These results suggest that some signaling pathways, such as the activation of ERK through BCR, are functional in B-CLL cells despite the extensive impairment of signaling pathways.
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PMID:Activation of extracellular signal-regulated kinase through B-cell antigen receptor in B-cell chronic lymphocytic leukemia. 1209 52

T-cell death, which occurs either for ontogenic T-cell selection or for activated T-cell elimination, is normally induced through binding of a specific ligand to cell-surface T-cell receptor for crosslinkage. Heavy metals and carbonyl compounds that bind to protein-reactive groups such as cysteine sulfhydryl groups and lysine epsilon-amino groups may also induce crosslinkage of cell-surface proteins, in part replacing or modifying the ligand-mediated action. This chemical event has been found to accompany clustering of membrane rafts, to which signal-transducing elements such as glycosylphosphatidylinositol-anchored proteins and Src family protein tyrosine kinases (PTKs) are attached, and to trigger the signal transduction for apoptotic T-cell death, inducing mitochondrial membrane potential reduction, caspase activation and DNA fragmentation. As signals potentially upstream of this signaling, activations of PTKs and mitogen-activated protein (MAP) family kinases and production of reactive oxygen species (ROS) were induced following the cell-surface event, and crucial roles of activation of c-Jun amino-terminal kinase and apoptosis signal-regulating kinase 1 by a redox-linked mechanism in the cell-death signaling were demonstrated. Intriguingly, ROS production as well as PTK/MAP family kinase activation occurred in a membrane raft integrity-dependent manner. The redox-linked and cell surface-oriented signal delivery pathway demonstrated here may play an important role in induction of immune disorders by protein reactive group-binding chemicals.
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PMID:Redox-linked cell surface-oriented signaling for T-cell death. 1221 11

Infection of bovine T cells and B cells with the intracellular protozoan parasite Theileria parva induces a transformed phenotype with characteristics comparable to leukemic cells. The transformed phenotype reverts on drug-induced parasite death, and the cured lymphocytes acquire a resting phenotype and eventually die by apoptosis if not further stimulated. Here, we show that both lymphocyte proliferation and activation of the transcription factor AP-1 are mediated by Src-family protein tyrosine kinases (PTKs) in a parasite-dependent fashion. Src-family PTKs are known to be present in glycolipid-enriched microdomains (GEMs), also called lipid rafts, and to be negatively regulated by PTK Csk complexed to tyrosine-phosphorylated transmembrane adapter protein PAG (phosphoprotein associated with GEMs) also called Cbp (Csk-binding protein). We, therefore, purified GEMs from proliferating infected B cells and from growth-arrested cells that had been drug-cured of parasites. Proliferation arrest led to a striking increase of PAG/Cbp expression; correspondingly, the amount of Csk associated with PAG/Cbp in GEMs increased markedly, whereas PTK Hck accumulation in GEM fractions did not alter on growth arrest. We propose that Theileria-induced lymphocyte proliferation and permanent activation of Hck stems from down-regulation of PAG/Cbp and the concomitant constitutive loss of the negative regulator Csk from the GEMs of transformed B cells.
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PMID:Constitutive exclusion of Csk from Hck-positive membrane microdomains permits Src kinase-dependent proliferation of Theileria-transformed B lymphocytes. 1241 11

Signaling molecules such as p21(ras) (Ras), mitogen-activated protein kinase (MAPK), and Akt kinase play pivotal roles in the proliferation and survival of lymphoid cells in response to many kinds of stimulation. It is not fully understood, however, how these molecules participate in the growth of malignant lymphoid cells. We determined whether Ras, MAPKs such as extracellular signal-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK), and p38 MAPK, and Akt kinase are activated in B-cell tumors, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, Burkitt-like lymphoma, diffuse large B-cell lymphoma, and plasma cell leukemia. We found that Lyn protein tyrosine kinase was constitutively phosphorylated on tyrosine, and that ERK and p38 MAPK were constitutively active in all cases of the B-cell tumor. In contrast, activation of Ras and Akt kinase was found in limited cases, and JNK kinase activity was not observed in any case. These results suggest that ERK and p38 play roles in the oncogenesis of B-cell tumors.
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PMID:Constitutive activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase in B-cell lymphoproliferative disorders. 1277 25

Hexachlorobenzene (HCB) is a lipophilic chemical compound that is widely distributed in the environment. HCB is known to cause liver tumors in experimental animals. In the present study the in vivo effect of HCB treatment on ornithine decarboxylase (ODC) and protein tyrosine kinase (PTK) activities, free polyamine content, and c-Myc, c-Fos, and c-Jun protein levels in rat liver were investigated. HCB (1000 mg/kg body weight) increased hepatic immunodetectable c-Myc, c-Fos, and c-Jun levels after 6 h, and ODC activity and spermine and putrescine content after 18 and 24 h, while maximum stimulation of PTK activity occurred at 12 h. PTK and ODC activities varied in a dose-dependent manner. The time-course of c-Myc, c-Fos, and c-Jun protein levels was different for each proto-oncogene. They were all elevated at the second day of treatment, while only c-Fos and c-Jun remained elevated after 10 days of HCB exposure. These data jointly suggest that the increase in ODC activity may be the consequence of proto-oncogene induction. The alterations in PTK activity suggest that the growth factor signal transduction pathway may be involved in the regulation of the proto-oncogene levels or/and ODC activity. The decrease in PTK activity after the first day, even in the presence of alpha-D-Difluoromethylornithine (DFMO), an inhibitor of ODC activity, suggests that it is not regulated by polyamines. These results may be relevant to the early molecular events involved in HCB tumor promoter activity in rat liver.
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PMID:Hexachlorobenzene-induced early changes in ornithine decarboxylase and protein tyrosine kinase activities, polyamines and c-Myc, c-Fos and c-Jun proto-oncogenes in rat liver. 1460 Feb 89

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


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