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)

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is a multifunctional cytokine and growth factor that has important roles in both pathological and physiological angiogenesis. VPF/VEGF induces vascular hyperpermeability, cell division, and other activities by interacting with two specific receptor tyrosine kinases, KDR/Flk-1 and Flt-1, that are selectively expressed on vascular endothelium. The signaling cascade that follows VPF/VEGF interaction with cultured endothelium is only partially understood but is known to result in increased intracellular calcium, activation of protein kinase C, and tyrosine phosphorylations of both receptors, phospholipase C-gamma (PLC-gamma) and phosphatidylinositol 3'-kinase. For many reasons, signaling events elicited in cultured endothelium may not mimic mediator effects on intact normal or tumor-induced microvessels in vivo. Therefore, we developed a system that would allow measurement of VPF/VEGF-induced signaling on intact microvessels. We used mouse mesentery, a tissue whose numerous microvessels are highly responsive to VPF/VEGF and that we found to express Flk-1 and Flt-1 selectively. At intervals after injecting VPF/VEGF i.p., mesenteries were harvested, extracted, and immunoprecipitated. Immunoblots confirmed that VPF/VEGF induced tyrosine phosphorylation of several proteins in mesenteric microvessels as in cultured endothelium: Flk-1; PLC-gamma; and mitogen-activated protein kinase. Similar phosphorylations were observed when mesentery was exposed to VPF/VEGF in vitro, or when mesenteries were harvested from mice bearing the mouse ovarian tumor ascites tumor, which itself secretes abundant VPF/VEGF. Other experiments further elucidated the VPF/VEGF signaling pathway, demonstrating phosphorylation of both PYK2 and focal adhesion kinase, activation of c-jun-NH2-kinase with phosphorylation of c-Jun, and an association between Flk-1 and PLC-gamma. In addition, we demonstrated translocation of mitogen-activated protein kinase to the cell nucleus in cultured endothelium. Taken together, these experiments describe a new model system with the potential for investigating signaling events in response to diverse mediators on intact microvessels in vivo and have further elucidated the VPF/VEGF signaling cascade.
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PMID:Vascular permeability factor/vascular endothelial growth factor-mediated signaling in mouse mesentery vascular endothelium. 951 16

Kaposi's sarcoma (KS) spindle cell growth and spread have been reported to be modulated by various cytokines as well as the human immunodeficiency virus (HIV) gene product Tat. Recently, HIV-1 Tat has been shown to act like a cytokine and bind to the Flk-1/KDR receptor for the vascular endothelial growth factor A (VEGF-A), which is expressed by KS cells. We have characterized signal transduction pathways stimulated by HIV-1 Tat upon its binding to surface receptors on KS cells. We observed that stimulation in KS 38 spindle cells resulted in tyrosine phosphorylation and activation of the Flk-1/KDR receptor. We also report that HIV-1 Tat treatment enhanced the phosphorylation and association of proteins found in focal adhesions, such as the related adhesion focal tyrosine kinase RAFTK, paxillin, and p130(cas). Further characterization revealed the activation of mitogen-activated protein kinase, c-Jun amino-terminal kinase (JNK), and Src kinase. HIV-1 Tat contains a basic domain which can interact with growth factor tyrosine kinase receptors and a classical RGD sequence which may bind to and activate the surface integrin receptors for fibronectin and vitronectin. We observed that stimulation of KS cells with basic as well as RGD sequence-containing Tat peptides resulted in enhanced phosphorylation of RAFTK and activation of MAP kinase. These studies reveal that Tat stimulation activates a number of signal transduction pathways that are associated with cell growth and migration.
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PMID:Human immunodeficiency virus tat modulates the Flk-1/KDR receptor, mitogen-activated protein kinases, and components of focal adhesion in Kaposi's sarcoma cells. 962 Oct 77

The expression of vascular endothelial growth factor mRNA and protein is regulated by a number of agents including growth factors, cytokines, and phorbol esters. Here we report that vascular endothelial growth factor is able to increase its own level in cultured human dermal microvascular endothelial cells. Accumulation of vascular endothelial growth factor mRNA and polypeptide can be detected as early as 4 h after addition of vascular endothelial growth factor to the cell culture medium. The autocrine action of vascular endothelial growth factor appears to be mediated by the KDR receptor. The increase of its own message by vascular endothelial growth factor is blocked by the transcription inhibitor actinomycin D. Transient transfection experiments performed with human dermal microvascular endothelial cells and using a 3.2 kb human vascular endothelial growth factor promoter fragment showed that vascular endothelial growth factor auto-induction can be mimicked at the promoter level. This indicates that the observed vascular endothelial growth factor mRNA increase after vascular endothelial growth factor treatment is occurring at the level of transcription. Furthermore, vascular endothelial growth factor auto-induction is inhibited by PD 098059, showing that phosphorylation events, catalyzed by mitogen activated protein kinases, are a prerequisite for the vascular endothelial growth factor effect. Examination of extracellular signal-regulated kinase and c-Jun N-terminal protein kinase catalytic activities showed that both enzymes have to be activated to mediate the vascular endothelial growth factor signal. Our data demonstrate for the first time the existence of an autocrine loop for vascular endothelial growth factor in endothelial cells. Most probably this represents an amplification mechanism for the action of vascular endothelial growth factor in the microvascularization process.
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PMID:An autocrine loop mediates expression of vascular endothelial growth factor in human dermal microvascular endothelial cells. 1128 18

Isolation of endothelial progenitors from human umbilical cord blood generated great hope in vascular tissue engineering. However, before clinical use, progenitor derived endothelial cells (PDECs) have to be compared with mature endothelial cells (ECs). The aim of this study was to explore the behavior of PDECs exposed to a proinflammatory cytokine (interleukin-1alpha; IL-1alpha) according to the mitogen-activated protein (MAP) kinase and nuclear factor (NF)-kappaB signal transduction pathways as well as procoagulant activity (PCA). CD34(+) mononuclear cells were isolated using magnetic beads, cultured, and compared with human saphenous vein ECs (HSVECs). PDECs express endothelial markers: CD31, VE-cadherin, von Willebrand factor, KDR, and incorporate acetylated low-density lipoprotein (Dil-Ac-LDL). IL-1alpha similarly activates c-Jun N-terminal protein kinase (JNK) and p38 pathways in HSVECs and PDECs, whereas extracellular signal-related kinase (ERK)1/2 phosphorylation is lower in PDECs than in HSVECs. Low ERK1/2 phosphorylation in PDECs was specific to IL-1alpha as vascular endothelial growth factor (VEGF) similarly stimulated ERK1/2 pathway. With respect to inhibitor of NF-kappa B (Ikappa B) degradation, NF-kappa B translocation and phosphorylation, the NF-kappa B pathway is comparable in HSVECs and PDECs after stimulation. PCA and tissue factor level induced by IL-1alpha are lower in PDECs than in HSVECs. Thus, our data show that PDECs display the characteristics of functional mature ECs under IL-1alpha stimulation. However, we observed significant differences between PDECs and HSVECs related to both ERK1/2 pathway activation and tissue factor production.
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PMID:Signal transduction and procoagulant state of human cord blood--progenitor-derived endothelial cells after interleukin-1alpha stimulation. 1757 11

A 10,000 member peptide nucleic acid (PNA) encoded peptide library was prepared, treated with the Abelson tyrosine kinase (Abl), and decoded using a DNA microarray and a fluorescently labeled secondary antiphosphotyrosine antibody. A dual-color approach ensured internal referencing for each and every member of the library and the generation of robust data sets. Analysis identified 155 peptides (out of 10,000) that were strongly phosphorylated by Abl in full agreement with known Abl specificities. BLAST analysis identified known cellular Abl substrates such as c-Jun amino-terminal kinase as well as new potential target proteins such as the G-protein coupled receptor kinase 6 and diacylglycerol kinase gamma. To illustrate the generalization of this approach, two other tyrosine kinases, human epidermal growth factor 2 (Her2) and vascular endothelial growth factor receptor 2/kinase insert domain protein receptor (VEGFR2/KDR), were profiled allowing characterization of specific peptide sequences known to interact with these kinases; under these conditions Her2 was demonstrated to have a marked preference for D-proline perhaps offering a unique means of targeting and inhibiting this kinase.
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PMID:A 10,000 member PNA-encoded peptide library for profiling tyrosine kinases. 1815 68

c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) is involved in the regulation of various cellular functions including cell cycle, proliferation, apoptosis. However, whether JNK/SAPK directly regulates the angiogenesis of human umbilical vein endothelial cells (HUVECs) induced by vascular endothelial growth factor A (VEGFA) has not yet been fully elucidated. Our present study firstly demonstrated VEGFA-induced angiogenic responses including the increase of cell viability, migration, and tube formation with a concentration-dependent manner in HUVECs. Further results showed that VEGFA induced the activation of JNK/SAPK, p38 kinase and extracellular signal-regulated kinases 1 and 2 (ERK1/2), while JNK/SAPK inhibitor SP600125 and specific siRNA both blocked all those angiogenic effects induced by VEGFA. Furthermore, VEGFA induced the phosphorylation of ASK1, SEK1/MKK4, MKK7, and c-Jun, which are upstream or downstream signals of JNK/SAPK. In addition, in vivo matrigel plug assay further showed that SP600125 inhibited VEGFA-induced angiogenesis. Further results showed that SP600125 and JNK/SAPK siRNA decreased VEGFA-induced VEGFR2 (Flk-1/KDR) sustained phosphorylation in HUVECs. Taken together, all these results demonstrate that JNK/SAPK regulates VEGFA-induced VEGFR2 sustained phosphorylation, which plays important roles in VEGFA-induced angiogenesis in HUVECs.
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PMID:c-Jun N-terminal kinase mediated VEGFR2 sustained phosphorylation is critical for VEGFA-induced angiogenesis in vitro and in vivo. 2259 17