Identification of genes that mediate steroid- and TNF-triggered non-apoptotic cell death. Gautam Das, Tsun-Kai Chang, Sudeshna Dutta, Charles Nelson, Emily Clough, Cheng-Yu Lee, Daniel Caffrey, Eric Baehrecke. Cancer Biology, University of Massachusetts Medical School, Worcester, MA.

   Programmed cell death is important for development, elimination of abnormal cells, and is altered in disorders including cancer. Although much is known about apoptosis, less is known about non-apoptotic cell death involving autophagy and necrosis. Here we investigate steroid-triggered cell death during development where DNA binding proteins influence target genes that control cell death. The steroid-response protein E93, a helix-turn-helix transcription factor, is necessary and sufficient for non-apoptotic cell death. We use genome-wide E93 DNA binding combined with gene expression analyses in E93 mutants to identify target genes, and show that E93 binds to a novel DNA sequence motif in target genes that control cell death. Significantly, we present evidence for tumor necrosis factor-triggered non-apoptotic cell death that is mediated by E93 and a novel target gene. This is the first evidence of genes that appear to contribute to caspase- and autophagy-independent programmed cell death under physiological conditions during development.