title: Human-gyrovirus-Apoptin triggers mitochondrial death pathway--Nur77 is required for apoptosis triggering.
abstract: The human gyrovirus derived protein Apoptin (HGV-Apoptin) a homologue of the chicken anemia virus Apoptin (CAV-Apoptin), a protein with high cancer cells selective toxicity, triggers apoptosis selectively in cancer cells. In this paper, we show that HGV-Apoptin acts independently from the death receptor pathway as it induces apoptosis in similar rates in Jurkat cells deficient in either FADD (fas-associated death domain) function or caspase-8 (key players of the extrinsic pathway) and their parental clones. HGV-Apoptin induces apoptosis via the activation of the mitochondrial intrinsic pathway. It induces both mitochondrial inner and outer membrane permebilization, characterized by the loss of the mitochondrial potential and the release into cytoplasm of the pro-apoptotic molecules including apoptosis inducing factor and cytochrome c. HGV-Apoptin acts via the apoptosome, as lack of expression of apoptotic protease-activating factor 1 in murine embryonic fibroblast strongly protected the cells from HGV-Apoptin-induced apoptosis. Moreover, QVD-oph a broad-spectrum caspase inhibitor delayed HGV-Apoptin-induced death. On the other hand, overexpression of the anti-apoptotic BCL-XL confers resistance to HGV-Apoptin-induced cell death. In contrast, cells that lack the expression of the pro-apoptotic BAX and BAK are protected from HGV-Apoptin induced apoptosis. Furthermore, HGV-Apoptin acts independently from p53 signal but triggers the cytoplasmic translocation of Nur77. Taking together these data indicate that HGV-Apoptin acts through the mitochondrial pathway, in a caspase-dependent manner but independently from the death receptor pathway.
authors.affiliation: Department of Clinical and Experimental Medicine (IKE), Division of Cell Biology, and Integrative Regenerative Medicine Center (IGEN), Linköping University, Linköping Sweden; Department of Biology, Faculty of Sciences, Tunis University, Tunis, Tunisia.
authors.forename: Wiem
authors.initials: W
authors.lastname: Chaabane
authors.affiliation: Department of Clinical and Experimental Medicine (IKE), Division of Cell Biology, and Integrative Regenerative Medicine Center (IGEN), Linköping University, Linköping Sweden; Inst. of Automatic Control, Silesian Univ. of Technology, Gliwice, Poland.
authors.forename: Artur
authors.initials: A
authors.lastname: Cieślar-Pobuda
authors.affiliation: Department of Biology, Faculty of Sciences, Tunis University, Tunis, Tunisia.
authors.forename: Mohamed
authors.initials: M
authors.lastname: El-Gazzah
authors.affiliation: Department of Clinical and Experimental Medicine (IKE), Division of Cell Biology, and Integrative Regenerative Medicine Center (IGEN), Linköping University, Linköping Sweden.
authors.forename: Mayur V
authors.initials: MV
authors.lastname: Jain
authors.affiliation: Inst. of Automatic Control, Silesian Univ. of Technology, Gliwice, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Rzeszowska-Wolny
authors.affiliation: Department of Biomedical Engineering, Linköping University, Linköping Sweden.
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Rafat
authors.affiliation: Department of Chemistry, University of Manitoba, Winnipeg, Canada.
authors.forename: Joerg
authors.initials: J
authors.lastname: Stetefeld
authors.affiliation: Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Canada.
authors.forename: Saeid
authors.initials: S
authors.lastname: Ghavami
authors.affiliation: Department of Clinical and Experimental Medicine (IKE), Division of Cell Biology, and Integrative Regenerative Medicine Center (IGEN), Linköping University, Linköping Sweden; Department of Pathology, Pomeranian Medical University, Szczecin, Poland. Electronic address: marek.los@liu.se.
authors.forename: Marek J
authors.initials: MJ
authors.lastname: Los
mesh_terms: D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D046810:Gyrovirus / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism*; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D053218:Receptors, Death Domain / Q000378:metabolism; D015398:Signal Transduction; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D019253:Proto-Oncogene Proteins c-bcl-2; D053218:Receptors, Death Domain; D014764:Viral Proteins; D045304:Cytochromes c; D020169:Caspases