Aven blocks DNA damage-induced apoptosis by stabilising Bcl-xL.
Induction of apoptosis by DNA-damaging agents involves the activation of mitochondrial apoptotic pathway. Aven has been identified as an antiapoptotic protein and has been shown to activate ATM in response to DNA damage. In this study, we demonstrated that enforced expression of Aven blocks UV-irradiation-, SN-38- or cisplatin-induced apoptosis upstream of mitochondria by stabilising Bcl-xL protein levels in breast cancer cells. Aven silencing by RNA interference markedly enhanced apoptotic response following treatment with DNA-damaging agents. Aven is complexed with Bcl-xL in untreated breast cancer cells and treatment with DNA-damaging agents led to decreased Aven/Bcl-xL interaction. Importantly, Bcl-xL was necessary for the prosurvival activity of Aven and depletion of Bcl-xL abrogated Aven-mediated protection against DNA damage-induced apoptosis. Analysis of breast cancer tissue microarrays revealed decreased Aven nuclear expression in breast cancer tissues compared with non-neoplastic breast tissues. In particular, we detected reduced nuclear expression of Aven in infiltrating ductal carcinoma and papillary carcinoma breast cancer subtypes compared with non-neoplastic breast tissues and infiltrating lobular breast cancer tissues. Our results suggest that Aven is an important mediator in DNA damage-induced apoptotic signalling in breast cancer cells and its nuclear expression is altered in breast cancer tissues, which may contribute to genomic instability in breast cancer tumours.
Kutuk
Ozgur
O
Biological Sciences and Bioengineering Program, Faculty of Natural Sciences and Engineering, Sabanci University, Istanbul, Turkey.
Temel
Sehime Gulsun
SG
Tolunay
Sahsine
S
Basaga
Huveyda
H
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D046228:Microarray Analysis; D008928:Mitochondria / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism*
C412506:AVEN protein, human; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D051020:bcl-X Protein