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Activation of the CPP32 protease in apoptosis induced by 1-beta-D-
arabinofuranosylcytosine and other DNA-damaging agents
R Datta, D Banach, H Kojima, RV Talanian, ES Alnemri, WW Wong and DW Kufe
Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard
Medical School, Boston, MA 02115, USA.
The response of human myeloid leukemia cells to treatment with 1-beta-
arabinofuranosylcytosine (ara-C) includes the induction of apoptosis. Ara-C
induced apoptosis is associated with proteolytic cleavage of
poly(ADP-ribose) polymerase (PARP) and protein kinase C (PKC) delta.
However, the signals involved in this response are unknown. The present
studies show that ara-C treatment of U-937 cells is associated with
induction of a protease activity that cleaves the tetrapeptides Ac-DEVD-
pNA and Ac-DMOD-pNA found at the cleavage sites of PARP and PKC delta,
respectively. The ara-C-induced protease activity was sensitive to
overexpression of the anti-apoptotic protein Bcl-xL and the baculovirus
protein p35. By contrast, overexpression of the cowpox virus protein CrmA
blocked apoptosis induced by engagement of the Fas receptor but not that
induced by ara-C. CrmA overexpression also had no detectable effect on
ara-C-induced cleavage of PKC delta. The results further show that ara-C
induces activation of the CPP32 protease by a CrmA- insensitive and
p35-sensitive mechanism. Similar results were obtained with cisplatinum,
etoposide, and camptothecin. These findings indicate that ara-C and other
DNA-damaging agents activate a CrmA-insensitive apoptotic pathway involving
CPP32 and that these signals differ from those associated with apoptosis
induced by the Fas receptor.
Volume 88,
Issue 6,
pp. 1936-1943,
09/15/1996
Copyright © 1996 by The American Society of Hematology
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Intracellular Acidification Triggered by Mitochondrial-derived Hydrogen Peroxide Is an Effector Mechanism for Drug-induced Apoptosis in Tumor Cells
J. Biol. Chem.,
January 5, 2001;
276(1):
514 - 521.
[Abstract]
[Full Text]
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R. Datta, E. Oki, K. Endo, V. Biedermann, J. Ren, and D. Kufe
XIAP Regulates DNA Damage-induced Apoptosis Downstream of Caspase-9 Cleavage
J. Biol. Chem.,
October 6, 2000;
275(41):
31733 - 31738.
[Abstract]
[Full Text]
[PDF]
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