Edited by: Stephen P. Hoffert
T. Fernandes-Alnemri, A. Takahashi, R. Armstrong, J. Krebs, L. Fritz, K.J. Tomaselli, L. Wang, Z. Yu, C.M. Croce, G. Salveson, W.C. Earnshaw, G. Litwack, E.S. Alnemri, "Mch3, a novel human apoptotic cysteine protease highly related to CPP32," Cancer Research, 55:6045-52, 1995. (Cited in more than 140 publications through November 1997)
Comments by Emad S. Alnemri, Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia
In the past five years, knowledge of apoptosis, or programmed cell death, has advanced rapidly and attracted wide attention, as it seems to touch on many areas of cell research. Through apoptosis, the tadpole loses its tail and becomes a frog. In human embryos, apoptosis carves fingers from mitt-like hands. It is a fundamental biological process that plays a critical role in the normal development of multicellular organisms through cellular differentiation and tissue homeostasis.
INSIGHTS ON DEATH: Emad Alnemri has led research teams that discovered six of at least 10 proteins essential in apoptosis.
At the molecular level, a family of at least 10 proteins or caspases, which make up the basic structure of the apoptotic cascade or sequence, has been identified in humans. Six of these have been discovered by Alnemri's team (E.S. Alnemri, Journal of Cellular Biochemistry, 64:33-44, 1997; S.M. Srinivasula et al., Journal of Biological Chemistry, 271:27099-106, 1996). These death-related proteins are Mch2, Mch3, Mch4, Mch5, Mch6, and the well-known caspase CPP32. In a multicellular organism, the proteolytic or protein-cleaving activity of these proteins is needed to fragment and shrink unwanted dying cells so they can be scavenged by neighboring cells.
Mch3 was the third apoptotic protein identified in Alnemri's laboratory. Interestingly, Mch3 is similar to CPP32 with respect to its amino acid sequence and its ability to cleave a DNA repair enzyme called PARP. Previously, CPP32 was believed to be the "death protease" because of its ability to cleave PARP. Alnemri's team observed not only that Mch3 was able to cleave PARP as efficiently as CPP32, but also that the recombinant subunits of Mch3 were able to substitute for recombinant subunits of CPP32. Like CPP32, Mch3 is poorly inhibitable by the cowpox virus antiapoptotic protein CrmA. Such similarity between CPP32 and Mch3 suggests that Mch3 may well substitute for CPP32 activity. Tissues and cell lines like breast carcinoma MCF7, which do not express high levels of CPP32, may in fact have their CPP32-like activity contributed by Mch3.
The discovery by Alnemri's research team has received significant attention because it could explain why CPP32-deficient mice experience abnormal growth only in the brain. In studies directed by Richard A. Flavell, a Howard Hughes Medical Institute investigator and an immunobiologist at Yale University School of Medicine, CPP32-deficient mice died at one to three weeks of age owing to abnormal tissue growth in the brain (K. Kuida et al., Nature, 384:368-72, 1996). But researchers were surprised to find that these mice often experienced normal developmental apoptosis apart from abnormal brain growth, suggesting that MCH3 might have been able to take over the role of CPP32 in those tissues. Ironically, Alnemri's research team had observed that the brain is the only tissue in which the lowest levels of Mch3 could be found.
"Presumably, this close structural and functional identity between Mch3 and CPP32 is what largely attracted the attention of apoptosis researchers," Alnemri explains. "In general, however, all caspases, their associated molecules [activators and inhibitors], and their substrates have received fairly significant global attention in this highly popular field, which is currently at the cutting edge of science."