Specificities of CD40 signaling: Involvement of TRAF2 in CD40-induced NF-κB activation and intercellular adhesion molecule-1 up-regulation

Abstract

Several tumor necrosis factor receptorassociated factor (TRAF) family proteins including TRAF2, TRAF3, TRAF5, and TRAF6, as well as Jak3, have been implicated as potential mediators of CD40 signaling. An extensive in vitro binding study indicated that TRAF2 and TRAF3 bind to the CD40 cytoplasmic tail (CD40ct) with much higher affinity than TRAF5 and TRAF6 and that TRAF2 and TRAF3 bind to different residues of the CD40ct. Using CD40 mutants incapable of binding TRAF2, TRAF3, or Jak3, we found that the TRAF2-binding site of the CD40ct is critical for NF-B and stress-activated protein kinase activation, as well as the up-regulation of the intercellular adhesion molecule-1 (ICAM-1) gene, whereas binding of TRAF3 and Jak3 is dispensable for all of these functions. Overexpression of a dominantly active IB␣ strongly inhibited CD40-induced NF-B activation, ICAM-1 promoter activity, and cell-surface ICAM-1 up-regulation. These studies suggest a potential signal transduction pathway from the CD40 receptor to the transcriptional activation of the ICAM-1 gene.

CD40 on Adult Human Airway Epithelial Cells: Expression and Proinflammatory Effects

“…Although other mediators not investigated in the present study may be produced following activation via CD40, IL-6 and IL-8 can be considered typical proinflammatory signals and have the capability of recruiting and/or activating lymphocytes, macrophages, granulocytes, and endothelial cells (41,42).…”

Expression of the Tumor Necrosis Factor Receptor-Associated Factors (TRAFs) 1 and 2 is a Characteristic Feature of Hodgkin and Reed-Sternberg Cells

“…Much like the case of LMP1, interaction of CD30 with TRAF1 and TRAF2 results in significant amplification of NF-B signaling (3,4,14). Similarly, stimulation of both CD40 and TNF-R2 also result in NF-B activation mediated by TRAF2 (5,6,13). Interestingly, TRAF6 protein, as found in all three of our HD cell lines, can also amplify NF-B signaling via interaction with CD40 (1,18).…”

“…In mammalian cells, the tumor necrosis factor (TNF) receptor-associated factor (TRAF) family consists of a group of six adapter proteins (TRAF1-TRAF6) that participate in the intracellular signaling activity of several members of the TNF receptor (TNFR) superfamily, including the TNF receptor 2 (TNF-R2), CD30, CD40, the lymphotoxin-␤ receptor, and the Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1; [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. Structurally, TRAF proteins are composed of an N-terminal cysteine/histidine-rich region containing zinc RING and/or zinc finger motifs, a central coiled coil region, and a C-terminal homology region that defines the TRAF family (1,2,10,11,13).…”

Upregulation of Bcl-x and Bfl-1 as a potential mechanism of chemoresistance, which can be overcome by NF-κB inhibition

“…In all three treatments, parental A549 cells were resistant to the pro-death e ects of chemotherapy agents, as assessed by MTT Figure 1 TNF-a-mediated upregulation of Bcl-x and B¯-1 in A549 cells requires NF-kB signaling. (a) A549 cells and the derived 42-7-8 cells were treated with 50 ng/ml of TNF-a for the indicated times, and nuclear extracts were prepared and analysed for binding activity to the H2 probe using previously published protocols (Lee et al, 1999b). 42-7-8 cell lines were generated from parental A549 cells by introduction of constructs encoding for the reverse tet-activator and also for the IkB mutant driven by a tetresponsive promoter.…”

“…(a) Establishing 42-7-8 cell lines expressing Bcl-x or B¯-1 at physiological levels. 42-7-8 cells were virally transduced with a Bcl-x or B¯-1-expressing construct cloned into the pBABEpuro vector using previously published protocols (Lee et al, 1999b). Stable populations were selected with 2.5 mg/ml of puromycin, and expression levels of the exogenous genes were assessed for Bcl-x by Western analysis and for B¯-1 by Northern analysis.…”