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Prepublished online as a Blood First Edition Paper on December 19, 2002; DOI 10.1182/blood-2002-08-2485. This Article Full Text (PDF) All Versions of this Article: 2002-08-2485v1 101/8/3093    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Johnson, H. Articles by Ley, T. J Search for Related Content PubMed PubMed Citation Articles by Johnson, H. Articles by Ley, T. J Social Bookmarking                   What's this? Submitted August 13, 2002 Accepted December 7, 2002 Cell death induced by Granzyme C Hillary Johnson, Luca Scorrano, Stanley J Korsmeyer, and Timothy J Ley* Division of Oncology, Depts of Medicine & Genetics, Siteman Cancer Center, Washington University, St. Louis, MO, USA Departments of Pathology & Medicine, Howard Hughes Medical Institute, Harvard Medical School, Dana Farber Cancer Institute, Boston, MA, USA; Venetian Institute of Molecular Medicine, Via Orus, Padova, Italy Departments of Pathology & Medicine, Howard Hughes Medical Institute, Harvard Medical School, Dana Farber Cancer Institute, Boston, MA, USA * Corresponding author; email: tley{at}im.wustl.edu. Although the function of granzymes A and B have been defined, the functions the other highly expressed granzymes of murine cytotoxic lymphocytes (C, D, and F) have not yet been evaluated. In this report, we describe the ability of murine GzmC (which is most closely related to human granzyme H) to cause cell death. The induction of death requires its protease activity, and is characterized by the rapid externalization of phosphatidylserine, nuclear condensation and collapse, and single-stranded DNA nicking. The kinetics of these events are similar to those caused by Granzyme B, and its potency (defined on a molar basis) is also equivalent. The induction of death did not involve the activation of caspases, the cleavage of BID, or the activation of the CAD nuclease. However, Granzyme C did cause rapid mitochondrial swelling and depolarization in intact cells or in isolated mitochondria, and this mitochondrial damage was not prevented by cyclosporin A pretreatment. These results suggest that Granzyme C rapidly induces target cell death by attacking both nuclear and mitochondrial targets, and that these targets are distinct from those utilized by Granzyme B to cause classical apoptosis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? 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