A Small Activator of Apoptosis

Abstract

The mitochondrial caspase activation pathway regulates caspase-9, a protease that is required for programmed cell death. Various apoptotic stimuli can release cytochrome c from mitochondria and activate caspase-9 through the formation of a proapoptotic protein complex called the apoptosome. Jiang et al. (see the Perspective by Nicholson and Thornberry) discovered a proapoptotic compound through a high throughput chemical screen and then, using a combination of biochemical fractionation and biological tests, identified the molecules responsible for the drug's effect. An oncoprotein called prothymosin-α and a tumor suppressor protein called PHAP (for putative HLA-DR-associated proteins) inhibited or accelerated the apoptosome-caspase-9 pathway, respectively. The study points to the apoptosome as a potential target for drug development. X. Jiang, H.-E. Kim, H. Shu, Y. Zhao, H. Zhang, J. Kofron, J. Donnelly, D. Burns, S. Ng, S. Rosenberg, X. Wang, Distinctive roles of PHAP proteins and prothymosin-α in a death regulatory pathway. Science 299 , 223-226 (2003). [Abstract] [Full Text] D. W. Nicholson, N. A. Thornberry, Life and death decisions. Science 299 , 214-215 (2003). [Summary] [Full Text]