Huijun Z. Ring

Toso, a Cell Surface, Specific Regulator of Fas-Induced Apoptosis in T Cells

Fas is a surface receptor that can transmit signals for apoptosis. Using retroviral cDNA library-based functional cloning we identified a gene, toso, that blocks Fas-mediated apoptosis. Toso expression was confined to lymphoid cells and was enhanced after cell-specific activation processes in T cells. Toso appeared limited to inhibition of apoptosis mediated by members of the TNF receptor family and was capable of inhibiting T cell self-killing induced by TCR activation processes that up-regulate Fas ligand. We mapped the effect of Toso to inhibition of caspase-8 processing, the most upstream caspase activity in Fas-mediated signaling, potentially through activation of cFLIP. Toso therefore serves as a novel regulator of Fas-mediated apoptosis and may act as a regulator of cell fate in T cells and other hematopoietic lineages.

Molecular cloning, mapping to human chromosome 1 q21-q23, and cell binding characteristics of Spalpha, a new member of the scavenger receptor cysteine-rich (SRCR) family of proteins

CD5 and CD6, two type I cell surface antigens predominantly expressed by T cells and a subset of B cells, have been shown to function as accessory molecules capable of modulating T cell activation. Here we report the cloning of a cDNA encoding Spα, a secreted protein that is highly homologous to CD5 and CD6. Spα has the same domain organization as the extracellular region of CD5 and CD6 and is composed of three SRCR (scavenger receptor cysteine rich) domains. Chromosomal mapping by fluorescence in situ hybridization and radiation hybrid panel analysis indicated that the gene encoding Spα is located on the long arm of human chromosome 1 at q21-q23 within contig WC1.17. RNA transcripts encoding Spα were found in human bone marrow, spleen, lymph node, thymus, and fetal liver but not in non-lymphoid tissues. Cell binding studies with an Spα immunoglobulin (Spα-mIg) fusion protein indicated that Spα is capable of binding to peripheral monocytes but not to T or B cells. Spα-mIg was also found to bind to the monocyte precursor cell lines K-562 and weakly to THP-1 but not to U937. Spα-mIg also bound to the B cell line Raji and weakly to the T cell line HUT-78. These findings indicate that Spα, a novel secreted protein produced in lymphoid tissues, may regulate monocyte activation, function, and/or survival.

The human neuregulin-2 (NRG2) gene: cloning, mapping and evaluation as a candidate for the autosomal recessive form of Charcot-Marie-Tooth disease linked to 5q

Neuregulin-2 (NRG2) is a novel member of the neuregulin family of growth and differentiation factors. Through interaction with the ErbB family of receptors, neuregulin-2 induces the growth and differentiation of epithelial, neuronal, glial and other types of cells. In this study, we have cloned the human neuregulin-2 gene, and determined its genomic structure and alternative splicing patterns. By using radiation hybrid mapping panels, the human NRG2 gene was mapped to the D5S658–D5S402 region within 5q23–q33, close to an autosomal recessive form of demyelinating Charcot-Marie-Tooth (CMT) disease. The NRG2 gene was found to be on two yeast artificial chromosomes overlapping the candidate interval and was, thus, considered a good positional candidate for this form of CMT. When the entire neuregulin-2 coding sequence and splice junctions were explored, however, no mutation was identified in one CMT family linked to 5q23–q33. In addition, three intronic single nucleotide polymorphisms were identified in the NRG2 gene. Genotyping in two families localized the NRG2 gene outside of the revised candidate interval between D5S402–D5S210 and excluded NRG2 as the gene responsible for this form of CMT disease.