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Suppression of vascular permeability and inflammation by targeting of the transcription factor c-Jun
Fahmy RG Waldman A Zhang G Mitchell A Tedla N Cai H Geczy CR Chesterman CN Perry M Khachigian LM 《Nature biotechnology》2006,24(7):856-863
Conventional anti-inflammatory strategies induce multiple side effects, highlighting the need for novel targeted therapies. Here we show that knockdown of the basic-region leucine zipper protein, c-Jun, by a catalytic DNA molecule, Dz13, suppresses vascular permeability and transendothelial emigration of leukocytes in murine models of vascular permeability, inflammation, acute inflammation and rheumatoid arthritis. Treatment with Dz13 reduced vascular permeability due to cutaneous anaphylactic challenge or VEGF administration in mice. Dz13 also abrogated monocyte-endothelial cell adhesion in vitro and abolished leukocyte rolling, adhesion and extravasation in a rat model of inflammation. Dz13 suppressed neutrophil infiltration in the lungs of mice challenged with endotoxin, a model of acute inflammation. Finally, Dz13 reduced joint swelling, inflammatory cell infiltration and bone erosion in a mouse model of rheumatoid arthritis. Mechanistic studies showed that Dz13 blocks cytokine-inducible endothelial c-Jun, E-selectin, ICAM-1, VCAM-1 and VE-cadherin expression but has no effect on JAM-1, PECAM-1, p-JNK-1 or c-Fos. These findings implicate c-Jun as a useful target for anti-inflammatory therapies. 相似文献
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We have used phospho-specific antibodies to re-examine the multisite phosphorylation of c-Jun in murine RAW macrophages and embryonic fibroblasts. Our results indicate that JNK isoforms are required and sufficient for the phosphorylation of Thr91 and Thr93, as well as the phosphorylation of Ser63 and Ser73, in response to LPS or anisomycin in macrophages and TNFalpha or anisomycin in fibroblasts. However, the phorbol ester (TPA) and EGF-induced phosphorylation of Ser63 and Ser73 is mediated by ERK1/ERK2, as well as JNK1/JNK2, in fibroblasts from wild-type mice and by ERK1/ERK2 alone in fibroblasts from JNK-deficient mice. The phosphorylation of Thr239 is catalysed by GSK3 and the phosphorylation of Ser243 by an as yet unidentified protein kinase. The inhibition of GSK3 is not required for the dephosphorylation of Thr239 in response to LPS, and nor is the phosphorylation of Thr91 and Thr93 required for the TPA- or EGF-induced dephosphorylation of Thr239 in fibroblasts. The agonist-induced dephosphorylation of Thr239 may involve a conformational change that exposes Thr239 to dephosphorylation and/or the activation of a Thr239 phosphatase. 相似文献
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Induction of melanocyte-specific microphthalmia-associated transcription factor by Wnt-3a 总被引:11,自引:0,他引:11
Takeda K Yasumoto K Takada R Takada S Watanabe K Udono T Saito H Takahashi K Shibahara S 《The Journal of biological chemistry》2000,275(19):14013-14016
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Rb binds c-Jun and activates transcription. 总被引:3,自引:0,他引:3
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The forkhead transcription factor AFX activates apoptosis by induction of the BCL-6 transcriptional repressor. 总被引:12,自引:0,他引:12
Tracy Tzu-Ling Tang Donald Dowbenko Amanda Jackson Lisa Toney David A Lewin Alexander L Dent Laurence A Lasky 《The Journal of biological chemistry》2002,277(16):14255-14265