XIAP regulates DNA damage-induced apoptosis downstream of caspase-9 cleavage |
| |
Authors: | Datta R Oki E Endo K Biedermann V Ren J Kufe D |
| |
Institution: | Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. Rakesh_Datta@dfci.harvard.edu |
| |
Abstract: | The IAP (inhibitor of apoptosis) family of anti-apoptotic proteins regulates programmed cell death. Of the six known human IAP-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-beta-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 procaspase-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 XIAP functions downstream of procaspase-9 cleavage as an inhibitor of both proteolytically processed caspase-9 and -3 in the cellular response to genotoxic stress. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|