p53-dependent DNA damage-induced apoptosis requires Fas/APO-1-independent activation of CPP32β

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 inv...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1997-07, Vol.57 (13), p.2550-2554
Main Authors: FUCHS, E. J, MCKENNA, K. A, BEDI, A
Format: Article
Language:English
Subjects:
Ageing, cell death
Biological and medical sciences
Cell physiology
Fundamental and applied biological sciences. Psychology
Molecular and cellular biology
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Summary: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 CPP32 beta (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 CPP32 beta -related proteolysis, and normal thymocytes were protected from irradiation by Acetyl-Asp-Glu-Val-Asp-CHO (Ac-DEVD-CHO), a specific inhibitor of CPP32 beta . We next examined whether the Fas system is required for p53-dependent apoptosis and whether stimuli that induce activation of CPP32 beta 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 CPP32 beta -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 CPP32 beta by a mechanism independent of Fas/FasL interactions and suggest that immunological or molecular methods of activating CPP32 beta may be effective at inducing apoptosis in p53-deficient cancers that are resistant to conventional chemotherapy or irradiation.
ISSN:0008-5472
1538-7445