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Tumor Necrosis Factor Receptor-Associated Factor

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　TNFR（肿瘤坏死因子受体）超家族包括一系列受体分子，如TNFR1、TNFR2、NGFR、Fas、CD27、CD30、CD40、DR3、DR4、DR5、RANK、LT2βR、421BB 等许多成员，除LT2βR 外，均为Ⅰ型膜蛋白。近年来，在研究TNFR 超家族成员的细胞内信号传导机制方面取得了很大进展，同时也发现了许多重要的胞内蛋白分子。令人感兴趣的是，在已鉴定出的二十多个新分子中大多数分属两类独特的胞质信号传导分子，即含有死亡结构域（Death Domain）的蛋白分子和含有TNF 受体相关分子同源区（TNF receptor associated factor）的蛋白分子。对于TRAF（肿瘤坏死因子受体相关因子）家族，目前已发现人和鼠的TRAF 分子各有6 种，在C-elegans 中发现一种CeTRAF，果蝇中也有两种DTRAF1和DTRAF2。这些TRAF分子不仅有共同的结构特征，而且作为信号传导通路上游的接头分子在细胞内信号传导中起非常重要的作用。

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2. TRAF-1, -2, -3, -5, and -6 are induced in atherosclerotic plaques and differentially mediate proinflammatory functions of CD40L in endothelial cells.
OBJECTIVE: Several lines of evidence implicate CD40 ligand (CD40L, CD154) as a mediator and marker of atherosclerosis. This study investigated the involvement of tumor necrosis factor receptor-associated factors (TRAFs) in CD40 signaling in endothelial cells (ECs) and their expression in atheromata and cells involved in atherogenesis. METHODS AND RESULTS: CD40L enhanced the basal expression of TRAF-1, -2, -3, and 6, but not TRAF-5 in ECs. TRAFs associated with CD40 on ligation by CD40L. Study of ECs from TRAF-1, -2, and -5-deficient mice demonstrated functional involvement of TRAFs in ... Read More »
» Published in Arterioscler Thromb Vasc Biol. 2007 May;27(5):1101-7. Epub 2007 Mar 1.

3. Tumor necrosis factor receptor-associated factors (TRAFs).
Tumor necrosis factor receptor-associated factors (TRAFS) were initially discovered as adaptor proteins that couple the tumor necrosis factor receptor family to signaling pathways. More recently they have also been shown to be signal transducers of Toll/interleukin-1 family members. Six members of the TRAF family have been identified. All TRAF proteins share a C-terminal homology region termed the TRAF domain that is capable of binding to the cytoplasmic domain of receptors, and to other TRAF proteins. In addition, TRAFs 2-6 have RING and zinc finger motifs that are important for signaling ... Read More »
» Published in Oncogene. 2001 Oct 1;20(44):6482-91.

4. Differential regulation of CD40-mediated TNF receptor-associated factor degradation in B lymphocytes.
Engagement of CD40 on murine B cells by its ligand CD154 induces the binding of TNFR-associated factors (TRAFs) 1, 2, 3, and 6, followed by the rapid degradation of TRAFs 2 and 3. TRAF degradation occurs in response to signaling by other TNFR superfamily members, and is likely to be a normal regulatory component of signaling by this receptor family. In this study, we found that receptor-induced TRAF degradation limits TRAF2-dependent CD40 signals to murine B cells. However, TRAFs 1 and 6 are not degraded in response to CD40 engagement, despite their association with CD40. To better understand ... Read More »
» Published in J Immunol. 2005 Sep 15;175(6):3780-9.

5. Siah ubiquitin ligase is structurally related to TRAF and modulates TNF-alpha signaling.
Members of the Siah (seven in absentia homolog) family of RING domain proteins are components of E3 ubiquitin ligase complexes that catalyze ubiquitination of proteins. We have determined the crystal structure of the substrate-binding domain (SBD) of murine Siah1a to 2.6 A resolution. The structure reveals that Siah is a dimeric protein and that the SBD adopts an eight-stranded beta-sandwich fold that is highly similar to the TRAF-C region of TRAF (TNF-receptor associated factor) proteins. The TRAF-C region interacts with TNF-alpha receptors and TNF-receptor associated death-domain (TRADD) ... Read More »
» Published in Nat Struct Biol. 2002 Jan;9(1):68-75. Comment in: Nat Struct Biol. 2002 Jan;9(1):8-10.

6. Regulation of antiviral responses by a direct and specific interaction between TRAF3 and Cardif.
Upon recognition of viral infection, RIG-I and Helicard recruit a newly identified adapter termed Cardif, which induces type I interferon (IFN)-mediated antiviral responses through an unknown mechanism. Here, we demonstrate that TRAF3, like Cardif, is required for type I interferon production in response to intracellular double-stranded RNA. Cardif-mediated IFNalpha induction occurs through a direct interaction between the TRAF domain of TRAF3 and a TRAF-interaction motif (TIM) within Cardif. Interestingly, while the entire N-terminus of TRAF3 was functionally interchangeable with that of ... Read More »
» Published in EMBO J. 2006 Jul 26;25(14):3257-63. Epub 2006 Jul 6.

7. Upregulation of TRAF-3 by shear stress blocks CD40-mediated endothelial activation.
Atherosclerosis is an inflammatory disease of large arteries that is initiated through the activation of endothelium by proinflammatory mediators. CD40 receptor stimulation has been implicated in the pathogenesis of atherosclerosis. One of the most important atheroprotective stimuli is the viscous drag (shear stress) generated by the streaming blood acting on the endothelial monolayer. Here, we demonstrate that shear stress prevents CD40 ligand-induced endothelial cell activation, and we identify upregulation of TNF receptor-associated factor-3 (TRAF-3) as a potent CD40-inhibitory mechanism. ... Read More »
» Published in J Clin Invest. 2001 Nov;108(10):1451-8.

8. Inhibited neutrophil apoptosis: proteasome dependent NF-kappaB translocation is required for TRAF-1 synthesis
Neutrophil (PMN) apoptosis regulates local and systemic inflammation during sepsis. Tumor necrosis factor receptor-associated factors (TRAFs) have been implicated as mediators of apoptosis; however, the signaling pathways for their production in stimulated PMN are unclear. We hypothesize that NF-kappaB translocation is necessary for the induction of TRAF-1 in PMNs with prolonged survival. Neutrophils were isolated from the blood of healthy volunteers by Ficoll gradient centrifugation and red blood cell sedimentation. Neutrophil NF-kappaB was inhibited with a proteasome inhibitor, PSI-I. Cells ... Read More »
» Published in Shock. 2000 Sep;14(3):290-4.

9. Cellular responses to murine CD40 in a mouse B cell line may be TRAF dependent or independent.
Engagement of CD40 by its ligand induces IKK and mitogen-activated protein kinase (MAPK) phosphorylation and transcriptional activation, leading to activation and differentiation of B cells. These events are most likely transduced by adaptor molecules that are recruited to the CD40 cytoplasmic domain, called TNF receptor-associated factors (TRAF). We have engineered a chimeric CD40 molecule using the human extracellular sequence and the murine cytoplasmic domain to assess the contribution that specific TRAF binding domains provide to the cytoplasmic signaling functions of CD40. The data ... Read More »
» Published in Eur J Immunol. 2002 Jan;32(1):39-49.

10. Tumor necrosis factor receptor-associated factor (TRAF) 2 and its role in TNF signaling
Tumor necrosis factor (TNF) is the prototypic member of the TNF ligand family and has a key role in the regulation of inflammatory processes. TNF exerts its functions by interaction with the death domain-containing TNF-receptor 1 (TNF-R1) and the non-death domain-containing TNF-receptor 2 (TNF-R2), both members of a receptor family complementary to the TNF ligand family. Due to the prototypic features of the TNF receptors and their importance for the regulation of inflammation, the signal transduction mechanisms utilized by these receptors have been extensively studied. Several proteins that ... Read More »
» Published in Int J Biochem Cell Biol. 2001 Jan;33(1):19-32.