XIAP regulates DNA damage-induced apoptosis downstream of caspase-9 cleavage

R. Datta, Eiji Oki, K. Endo, V. Biedermann, J. Ren, D. Kufe

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

The IAP (inhibitor of apoptosis) family of anti-apoptotic proteins regulates programmed cell death. Of the six known human LAP-related proteins, XIAP is the most potent inhibitor. To study the mechanistic effects of XIAP on DNA damage-induced apoptosis, we prepared U-937 cells that stably overexpress XIAP. The results demonstrate that XIAP inhibits apoptosis induced by 1-[β-D-arabinofuranosyl]cytosine (ara-C) and other genotoxic agents. XIAP had no detectable effect on ara-C-induced release of mitochondrial cytochrome c and attenuated cleavage of precaspase-9. In addition, we show that ara-C induces the association of XIAP with the cleaved fragments of caspase-9 and thereby inhibition of caspase-9 activity. The results also demonstrate that ara-C induces cleavage of procaspase-3 by a caspase-8-dependent mechanism and that XIAP inhibits caspase-3 activity. These results demonstrate that functions downstream of procaspase-9 cleavage as an inhibitor of both proteolytically processed caspase-9 and -3 in the cellular response to genotoxic stress.

Original languageEnglish
Pages (from-to)31733-31738
Number of pages6
JournalJournal of Biological Chemistry
Volume275
Issue number41
DOIs
Publication statusPublished - Oct 13 2000
Externally publishedYes

Fingerprint

Caspase 9
Cytosine
DNA Damage
Caspase 3
Apoptosis
DNA
X-Linked Inhibitor of Apoptosis Protein
Apoptosis Regulatory Proteins
Caspase 8
Cell death
Cytochromes c
Cell Death

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

XIAP regulates DNA damage-induced apoptosis downstream of caspase-9 cleavage. / Datta, R.; Oki, Eiji; Endo, K.; Biedermann, V.; Ren, J.; Kufe, D.

In: Journal of Biological Chemistry, Vol. 275, No. 41, 13.10.2000, p. 31733-31738.

Research output: Contribution to journalArticle

Datta, R. ; Oki, Eiji ; Endo, K. ; Biedermann, V. ; Ren, J. ; Kufe, D. / XIAP regulates DNA damage-induced apoptosis downstream of caspase-9 cleavage. In: Journal of Biological Chemistry. 2000 ; Vol. 275, No. 41. pp. 31733-31738.
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AU - Oki, Eiji

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AU - Biedermann, V.

AU - Ren, J.

AU - Kufe, D.

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AB - The IAP (inhibitor of apoptosis) family of anti-apoptotic proteins regulates programmed cell death. Of the six known human LAP-related proteins, XIAP is the most potent inhibitor. To study the mechanistic effects of XIAP on DNA damage-induced apoptosis, we prepared U-937 cells that stably overexpress XIAP. The results demonstrate that XIAP inhibits apoptosis induced by 1-[β-D-arabinofuranosyl]cytosine (ara-C) and other genotoxic agents. XIAP had no detectable effect on ara-C-induced release of mitochondrial cytochrome c and attenuated cleavage of precaspase-9. In addition, we show that ara-C induces the association of XIAP with the cleaved fragments of caspase-9 and thereby inhibition of caspase-9 activity. The results also demonstrate that ara-C induces cleavage of procaspase-3 by a caspase-8-dependent mechanism and that XIAP inhibits caspase-3 activity. These results demonstrate that functions downstream of procaspase-9 cleavage as an inhibitor of both proteolytically processed caspase-9 and -3 in the cellular response to genotoxic stress.

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