No abstract

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.

Here we describe two mammalian transcription factors selectively expressed in the central nervous system. Both proteins, neuronal PAS domain protein (NPAS) 1 and NPAS2, are members of the basic helix-loop-helix-PAS family of transcription factors. cDNAs encoding mouse and human forms of NPAS1 and NPAS2 have been isolated and sequenced. RNA blotting assays demonstrated the selective presence of NPAS1 and NPAS2 mRNAs in brain and spinal cord tissues of adult mice. NPAS1 mRNA was first detected at embryonic day 15 of mouse development, shortly after early organogenesis of the brain. NPAS2 mRNA was first detected during early postnatal development of the mouse brain. In situ hybridization assays using brain tissue of postnatal mice revealed an exclusively neuronal pattern of expression for NPAS1 and NPAS2 mRNAs. The human NPAS1 gene was mapped to chromosome 19q13.2-q13.3, and the mouse Npas1 gene to chromosome 7 at 2 centimorgans. Similarly, the human NPAS2 gene was assigned to chromosome 2p11.2-2q13, and the mouse Npas2 gene to chromosome 1 at 21-22 centimorgans. The chromosomal regions to which human NPAS1 and NPAS2 map are syntenic with those containing the mouse Npas1 and Npas2 genes, indicating that the mouse and human genes are true homologs.Molecular biological studies reported during the past decade have identified a family of transcription factors designated basic helix-loop-helix (bHLH)-PAS proteins. Members of this protein family contain a bHLH DNA binding domain located on the amino-terminal side of a PAS domain. PAS is an acronym derived from the initial three proteins observed to contain this polypeptide motif: the period gene product of fruit flies (1-3), the aryl hydrocarbon receptor nuclear transporter (4), and the single-minded gene product of fruit flies (5). The PAS domain is approximately 260 amino acids in length and contains two direct repeats of about 60 amino acids (5).Biochemical studies of the aryl hydrocarbon (AH) receptor have provided evidence that it is directly regulated by xenobiotic compounds (reviewed in ref. 6). In its resting state, the AH receptor is retained in the cytoplasm in association with heat shock protein 90 (HSP90) (7). Upon exposure to xenobiotics, the AH receptor is released from HSP90 and dimerizes with the AH receptor nuclear transporter, a second bHLH-PAS domain protein critical to the function of the AH receptor (4, 8). The activated AH receptor͞AH receptor nuclear transporter heterodimer enters the nucleus and activates a battery of genes, including those encoding P450 enzymes that facilitate detoxification (9, 10). The PAS domain of the AH receptor performs three biochemical functions in this regulatory path-