Abstract:
:TRAIL is an endogenous death receptor ligand also used therapeutically because of its selective proapoptotic activity in cancer cells. In the present study, we examined chromatin alterations induced by TRAIL and show that TRAIL induces a rapid activation of DNA damage response (DDR) pathways with histone H2AX, Chk2, ATM, and DNA-PK phosphorylations. Within 1 h of TRAIL exposure, immunofluorescence confocal microscopy revealed gamma-H2AX peripheral nuclear staining (gamma-H2AX ring) colocalizing with phosphorylated/activated Chk2, ATM, and DNA-PK inside heterochromatin regions. The marginal distribution of DDR proteins in early apoptotic cells is remarkably different from the focal staining seen after DNA damage. TRAIL-induced DDR was suppressed upon caspase inhibition or Bax inactivation, demonstrating that the DDR activated by TRAIL is downstream from the mitochondrial death pathway. H2AX phosphorylation was dependent on DNA-PK, while Chk2 phosphorylation was dependent on both ATM and DNA-PK. Downregulation of Chk2 decreased TRAIL-induced cell detachment; delayed the activation of caspases 2, 3, 8, and 9; and reduced TRAIL-induced cell killing. Together, our findings suggest that nuclear activation of Chk2 by TRAIL acts as a positive feedback loop involving the mitochondrion-dependent activation of caspases, independently of p53.
journal_name
Mol Cell Bioljournal_title
Molecular and cellular biologyauthors
Solier S,Sordet O,Kohn KW,Pommier Ydoi
10.1128/MCB.00581-08subject
Has Abstractpub_date
2009-01-01 00:00:00pages
68-82issue
1eissn
0270-7306issn
1098-5549pii
MCB.00581-08journal_volume
29pub_type
杂志文章abstract::Lactoperoxidase was used to selectively radiolabel endocytic membrane. CHO cells were incubated with enzyme at 37 degrees C for 10 min to permit lactoperoxidase internalization. Radioiodination was done at 4 degrees C. About 90% of the radioiodinated products pelleted at 100,000 X g. From 12 to 15 different electropho...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Molecular and cellular biology
pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Molecular and cellular biology
pub_type: 杂志文章
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pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Molecular and cellular biology
pub_type: 杂志文章,收录出版
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更新日期:2014-01-01 00:00:00
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journal_title:Molecular and cellular biology
pub_type: 杂志文章
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pub_type: 杂志文章
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更新日期:2001-04-01 00:00:00
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pub_type: 杂志文章
doi:10.1128/mcb.17.1.10
更新日期:1997-01-01 00:00:00
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journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.13.8.4728
更新日期:1993-08-01 00:00:00
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journal_title:Molecular and cellular biology
pub_type: 杂志文章
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更新日期:2000-09-01 00:00:00
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journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.25.17.7412-7422.2005
更新日期:2005-09-01 00:00:00
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journal_title:Molecular and cellular biology
pub_type: 杂志文章
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更新日期:2010-02-01 00:00:00
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pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Molecular and cellular biology
pub_type: 杂志文章
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更新日期:2018-12-11 00:00:00
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journal_title:Molecular and cellular biology
pub_type: 杂志文章
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journal_title:Molecular and cellular biology
pub_type: 杂志文章
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更新日期:2005-04-01 00:00:00
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pub_type: 杂志文章
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更新日期:2002-05-01 00:00:00
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pub_type: 杂志文章
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pub_type: 杂志文章
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更新日期:1989-04-01 00:00:00
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pub_type: 杂志文章
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更新日期:2005-11-01 00:00:00
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journal_title:Molecular and cellular biology
pub_type: 杂志文章
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更新日期:2013-08-01 00:00:00