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Department of Pharmacology and the Jefferson Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
We have developed a PCR approach to clone new apoptotic Ced-3/Ice-like cysteine protease genes. This approach uses degenerate oligonucleotides encoding the highly conserved pentapeptides QACRG and GSWFI that are present in all known apoptotic cysteine proteases. Using this approach, we have cloned a novel apoptotic gene from human Jurkat T lymphocytes. The new gene encodes a 
34-kilodalton protein that is highly homologous to human CPP32, Caenorhabditis elegans cell death protein CED-3, mammalian Ich-1 (Nedd2), and mammalian interleukin-1ß converting enzyme. Because of its high homology to the C. elegans Ced-3 gene, we named the new gene mammalian Ced-3 homologue Mch2. Two Mch2 transcripts (Mch2
, 1.7 kb; Mch2ß, 1.4 kb) were detected in Jurkat T lymphocytes and other cell lines. We believe that the Mch2 transcript encodes the full-length Mch2, whereas the Mch2ß transcript encodes a shorter Mch2 isoform, probably as a result of alternative splicing. Like interleukin-1ß converting enzyme and CPP32, recombinant Mch2, but not Mch2ß, possesses protease activity, as determined by its ability to cleave the fluorogenic peptide DEVD-AMC. CPP32 and Mch2 can also cleave poly(ADP-ribose) polymerase in vitro, suggesting that these enzymes participate in poly(ADP-ribose) polymerase cleavage observed during cellular apoptosis. In addition, overexpression of recombinant Mch2, but not Mch2ß, induces apoptosis in Sf9 insect cells. Our data suggest that Mch2 is a Ced-3/interleukin-1ß converting enzyme-like cysteine protease and could be another important mediator of apoptosis in mammalian cells.
1 This work was supported by research Grant AI 35035-01 from the NIH.
2 To whom requests for reprints should be addressed, at Department of Pharmacology, Thomas Jefferson University, Bluemle Life Sciences Building, 233 S. 10th Street, Philadelphia, PA 19107.
Received 3/24/95. Accepted 5/19/95.
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