Crossed TRAILs

and colleagues have identified a protein called Hippi as one possible mediator of Huntington disease (HD) neuronal cell death. HD begins with expansion of the polyglutamine repeats in the huntingtin protein (Htt). This frees up Hip1 protein, which normally binds to Htt. Free Hip1 can then bind to the Hippi protein identified by Nicholson, and the two proteins join in a complex with procaspase 8, although this interaction appears to be indirect. Once two or more molecules of procaspase 8 are in close proximity, D Crossed TRAILs poptosis appeared to be a tale of many proteins but two distinct pathways. The extrinsic pathway leads from cell receptors to caspase 8, whereas the intrinsic pathway leads from cellular stresses (such as DNA damage) via mitochondria to caspase 9. But then came evidence that caspase 8 could help release cytochrome c from mitochondria. In new work, Xiangwei Wu and colleagues have added another link between the two pathways, and indicated that Smac, not cyt c , may be the critical protein to be released from mitochondria. Wu began his study by looking at the death ligand TRAIL. Apoptosis triggered by TRAIL was blocked by the antiapoptotic Bcl-xL and required the proapoptotic Bax—two proteins that act via mitochondria. Without Bax, TRAIL still activated caspase 8 but did not trigger release of cyt c or Smac from mitochondria. Of these two molecules, Smac is the most important for TRAIL's activity. The primary function of released cyt c is the activation of caspase 9, but Wu found that caspase 9 was not required for TRAIL-dependent apoptosis. In contrast, cytosolic Smac could overcome the requirement for Bax. Once in the cytosol, Smac appears to displace XIAP from caspase 3, allowing the final maturation of caspase 3 that was begun by caspase 8. With XIAP levels high in some cancer cells, additional activation of the mitochondrial pathway (e.g., by DNA-damaging agents) may help TRAIL to kill these cells. ᭿ A JAK/STAT invasion signaling pathway that is critical in fly eggs might be a key to understanding cancer cell metastasis, according to Debra Silver and Denise Montell (Johns Hopkins School of Medicine, Baltimore, MD). They have found that activation of the JAK/STAT signaling pathway triggers the migration of border cells, which start off at the anterior end of the egg chamber, travel in between the nurse cells, and end up at the anterior end of the oocyte. Once …