CD27, a member of the tumor necrosis factor receptor family, induces apoptosis and binds to Siva, a proapoptotic protein

Tumor necrosis factor receptor associated factors (TRAFs) play a variety of interesting and important roles in the regulation of B lymphocyte function. They act both as cytoplasmic regulatory molecules, and as signal transducers for receptors involved in both innate and adaptive humoral immune responses. In this brief review, we highlight the current state of knowledge of the diverse roles of TRAF molecules in the functions of B lymphocytes. CD40CD40 is the most well-studied member of the TNFR superfamily expressed by B lymphocytes, so its interactions with TRAF molecules have also been intensively investigated. B cell CD40 is important in the induction of B cell survival and expansion, immunoglobulin (Ig) production and isotype switching, upregulation of surface molecules involved in B cell antigen presentation, differentiation to B memory cells, and the production of various cytokines (reviewed in [1]. The TRAF molecules have been shown to contribute to each of these functions (reviewed in [2].In 1994, TRAF3 became the first cytoplasmic molecule demonstrated to associate with CD40 (reviewed in [2]). However, for many years, its roles in CD40 signaling were largely unknown, and are still not completely understood. TRAF3 -/-mice die shortly after birth, but adoptive transfer of fetal liver cells from these mice suggested that their B cells were capable of reconstituting the humoral response [3], implying that TRAF3 is not required to promote CD40-mediated antibody responses. This conclusion was supported by experiments in B cell lines demonstrating that inducible overexpression of TRAF3 inhibits both CD40 responses [4], and cooperation between CD40 and the BCR [5]. Subsequently, B cell lines made completely TRAF3-deficient via gene targeting by homologous recombination show no defects in CD40 signaling overall, and display enhanced CD40-mediated c-jun kinase (JNK) activation and IgM production [6]. Recently, mice made conditionally deficient in TRAF3 only in CD19+ B cells show no deficiencies in CD40 signaling in vitro and have enhanced antibody responses [7]. TRAF2 was initially demonstrated to bind CD40 by exogenous overexpression studies in adenocarcinoma cell lines, in which it promotes JNK activation and the activity of NF-κB reporter genes (reviewed in [2]. Because TRAF2 -/-mice have an early lethal phenotype [8],Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers

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Siva-1, as a p53-inducible gene, has been shown to induce extensive apoptosis in a number of different cell lines. Recent evidence suggests that Siva-1 functions as a part of the auto-regulatory feedback loop that restrains p53 through facilitating Mdm2-mediated p53 degradation. Also, Siva-1 plays an important role in suppressing tumor metastasis. Here we review the current understanding of Siva-1-mediated apoptotic signaling pathway. We also add comments on the p53-Siva-1 feedback loop, the novel function of Siva-1 in suppressing tumor metastasis, and their potential implications.