Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitogenic signals initiated at the plasma membrane are transmitted to the nucleus through an intricate signalling network. We identified the protooncoprotein Cot as a new component of mitogenic signalling cascades, which activates both the classic cytoplasmic cascade and the SAPK stress pathway. Wildtype and activated Cot phosphorylate and activate MEK-1 and SEK-1 in vitro. These findings are consistent with the sequence homology between Cot and the rat gene Tpl-2. Expression of oncogenic Cot in 293, NIH3T3 and PC12 cells leads to in vivo phosphorylation of endogenous c-Jun and Erk-1/2 suggesting that the serine/threonine kinase Cot functions beside c-Raf-1 and Mos as a direct activator of MEK-1. Furthermore, we have examined the biological effects of Cot on the phenotype of fibroblastic and neuronal cells. In order to test a potential c-Raf-1 dependency of Cot transformation, the effect of oncogenic Cot on Raf revertant CHP25 cells was determined. Cot could restore the transformed phenotype indicating that Cot transformation is not dependent on active c-Raf-1 and that Cot is not a target for the putative Raf inhibitor, which is presumably active in the revertant cell line. Expression of oncogenic versions of Raf as well as v-Mos leads to differentiation of PC12 cells. Cot also induces neurite outgrowth of PC12 cells. These data are consistent with the role of Cot in the classic mitogenic cascade and suggest that the simultaneously activated JNK/SAPK stress pathway has no antagonistic effects in this context.
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PMID:Cot protooncoprotein activates the dual specificity kinases MEK-1 and SEK-1 and induces differentiation of PC12 cells. 1005 Aug 76

The atheroprotective role of apolipoprotein E (apoE) is well established. During inflammation, expression of apoE in macrophages is reduced leading to enhanced atheromatous plaque development. In the present study, we investigated the signaling pathways involved in the repression of apoE gene expression in response to lipopolysaccharide (LPS) treatment, a condition that mimics the inflammatory stress, in mouse macrophages RAW 264.7. We identified Tpl-2 and MEKK1 as the kinases that are primarily responsible for the down-regulation of apoE promoter activity by LPS. Using a dominant negative form of IkappaB, we established that Tpl-2 and MEKK1 signaling pathways converge to NF-kappaB acting on the apoE core promoter -55/+73. In addition to NF-kappaB activation, LPS also activated c-Jun via its phosphorylation by JNK. The activity of the apoE promoter was repressed by c-Jun, whereas small interference RNA-mediated inhibition of endogenous c-Jun expression reversed the inhibitory effect of Tpl-2 on the apoE promoter. Transfection experiments and DNA binding assays showed that the binding site for c-Jun is in the -55/+73 region of the apoE promoter. Finally, we showed that LPS inhibited apoE gene expression via activation of the Tpl-2/MEK/ERK pathway acting on a different apoE promoter region. In summary, LPS represses apoE gene expression in macrophages via signaling pathways that involve the upstream kinases Tpl-2 and MEKK1, the intermediate mitogen-activated protein kinases ERK and JNK, and the downstream transcription factors AP-1 and NF-kappaB that inhibit the apoE promoter activity via distinct regions.
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PMID:Inflammatory signaling pathways regulating ApoE gene expression in macrophages. 1755 93