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Johns Hopkins Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287
In many cell types, the p53 tumor suppressor protein is required for the induction of apoptosis by DNA-damaging chemotherapy or radiation. Therefore, identification of the molecular determinants of p53-dependent cell death may aid in the design of effective therapies of p53-deficient cancers. We investigated whether p53-dependent apoptosis requires activation of CPP32ß (caspase 3), a cysteine protease that has been found to mediate apoptosis in response to ligation of the Fas molecule or to granzyme B, a component of CTL lytic granules. Irradiation-induced apoptosis was associated with p53-dependent activation of CPP32ß-related proteolysis, and normal thymocytes were protected from irradiation by Acetyl-Asp-Glu-Val-Asp-CHO (Ac-DEVD-CHO), a specific inhibitor of CPP32ß. We next examined whether the Fas system is required for p53-dependent apoptosis and whether stimuli that induce activation of CPP32ß induce apoptosis in p53-deficient cells. Thymocytes or activated T cells from Fas-deficient mice were resistant to apoptosis induced by ligation of Fas or CD3, respectively, but remained normally susceptible to irradiation. Thymocytes from p53-deficient mice, although resistant to DNA damage, remained sensitive to CPP32ß-mediated apoptosis induced by ligation of Fas or CD3, or by exposure to cytotoxic T cells. These results demonstrate that DNA damage-induced apoptosis of T cells requires p53-mediated activation of CPP32ß by a mechanism independent of Fas/FasL interactions and suggest that immunological or molecular methods of activating CPP32ß may be effective at inducing apoptosis in p53-deficient cancers that are resistant to conventional chemotherapy or irradiation.
1 This work was funded in part by a grant from the Alexander and Margaret Stewart Trust, Grant K08A101249 from the National Institute of Allergy and Infectious Diseases (to E. J. F.), and Grant 1 R29CA71660-01A1 from the National Cancer Institute (to A. B). A. B. is a recipient of a Passano Physician Scientist award, a Jose Carreras American Society of Hematology Scholar award, and grants from the American Cancer Society and the Wendy Will Case Cancer Fund.
2 To whom requests for reprints should be addressed, at 3-127 Johns Hopkins Oncology Center, 600 North Wolfe Street, Baltimore, MD 21287. Phone: (410) 955-8797; Fax: (410) 955-1969.
Received 3/24/97. Accepted 5/15/97.
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