Abstract
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 CPP32β (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 CPP32β-related proteolysis, and normal thymocytes were protected from irradiation by acetyl-Asp-Glu-Val-Asp-CHO (Ac-DEVD-CHO), a specific inhibitor of CPP32β. We next examined whether the Fas system is required for p53-dependent apoptosis and whether stimuli that induce activation of CPP32β 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 CPP32β-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 CPP32β by a mechanism independent of Fas/FasL interactions and suggest that immunological or molecular methods of activating CPP32β may be effective at inducing apoptosis in p53-deficient cancers that are resistant to conventional chemotherapy or irradiation.
Original language | English (US) |
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Pages (from-to) | 2550-2554 |
Number of pages | 5 |
Journal | Cancer Research |
Volume | 57 |
Issue number | 13 |
State | Published - Jul 1 1997 |
ASJC Scopus subject areas
- Oncology
- Cancer Research