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The antiapoptotic protein AAC‐11 interacts with and regulates Acinus‐mediated DNA fragmentation
Author(s) -
Rigou Patricia,
Piddubnyak Valeria,
Faye Audrey,
Rain JeanChristophe,
Michel Laurence,
Calvo Fabien,
Poyet JeanLuc
Publication year - 2009
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2009.106
Subject(s) - biology , fragmentation (computing) , dna fragmentation , acinus , dna , microbiology and biotechnology , dna binding protein , genetics , apoptosis , transcription factor , biochemistry , gene , programmed cell death , ecology , pancreas
The nuclear factor Acinus has been suggested to mediate apoptotic chromatin condensation after caspase cleavage. However, this role has been challenged by recent observations suggesting a contribution of Acinus in apoptotic internucleosomal DNA cleavage. We report here that AAC‐11, a survival protein whose expression prevents apoptosis that occurs on deprivation of growth factors, physiologically binds to Acinus and prevents Acinus‐mediated DNA fragmentation. AAC‐11 was able to protect Acinus from caspase‐3 cleavage in vivo and in vitro , thus interfering with its biological function. Interestingly, AAC‐11 depletion markedly increased cellular sensitivity to anticancer drugs, whereas its expression interfered with drug‐induced cell death. AAC‐11 possesses a leucine‐zipper domain that dictates, upon oligomerization, its interaction with Acinus as well as the antiapoptotic effect of AAC‐11 on drug‐induced cell death. A cell permeable peptide that mimics the leucine‐zipper subdomain of AAC‐11, thus preventing its oligomerization, inhibited the AAC‐11–Acinus complex formation and potentiated drug‐mediated apoptosis in cancer cells. Our results, therefore, show that targeting AAC‐11 might be a potent strategy for cancer treatment by sensitization of tumour cells to chemotherapeutic drugs.