The antiapoptotic protein AAC-11 interacts with and regulates Acinus-mediated DNA fragmentation.
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.
Rigou
Patricia
P
INSERM UMRS 940, Equipe Avenir, Université Paris 7, Institut de Génétique Moléculaire, Paris, France.
Piddubnyak
Valeria
V
Faye
Audrey
A
Rain
Jean-Christophe
JC
Michel
Laurence
L
Calvo
Fabien
F
Poyet
Jean-Luc
JL
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D061945:Caspase Inhibitors; D002460:Cell Line; D053938:DNA Fragmentation; D006801:Humans; D016350:Leucine Zippers; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping
C121310:ACIN1 protein, human; C108386:API5 protein, human; D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; D009687:Nuclear Proteins