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

Ephraim J Fuchs, Karen A. McKenna, Atul Bedi

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)2550-2554
Number of pages5
JournalCancer Research
Volume57
Issue number13
StatePublished - Jul 1 1997

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DNA Damage
Apoptosis
Thymocytes
Ligation
T-Lymphocytes
Tumor Suppressor Protein p53
Drug Therapy
Granzymes
Cysteine Proteases
Caspase 3
Proteolysis
Neoplasms
Cell Death
Radiation
DNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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p53-dependent DNA damage-induced apoptosis requires Fas/APO-1- independent activation of CPP32β. / Fuchs, Ephraim J; McKenna, Karen A.; Bedi, Atul.

In: Cancer Research, Vol. 57, No. 13, 01.07.1997, p. 2550-2554.

Research output: Contribution to journalArticle

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