title: Heat shock protein-70 neutralizes apoptosis inducing factor in Bcr/Abl expressing cells.
abstract: Bcr/Abl fusion protein is a hallmark of human chronic myeloid leukemia (CML). The protein can activate various signaling pathways to make normal cells transform malignantly and thus to facilitate tumorigenesis. It has been reported that heat shock protein-70 (HSP-70) can be served as an anti-apoptotic protein that suppresses Bax and Apo-2L/TRAIL. But it is unclear whether HSP-70 affects AIF-initiated apoptosis in Bcr/Abl expressing cells considering that HSP-70 is coincidentally over-regulated in these cells. Our findings supported that abundant HSP-70 in Bcr/Abl cells neutralizes AIF by segregating it from nucleus via direct interaction, leading to the failure of AIF initiating cell death and the silence of caspase-independent apoptotic pathway upon apoptotic induction. Moderate inhibition of HSP-70 expression by siRNA leads to Vp-16 triggered re-distribution of AIF in nucleus. In addition, AIF bears a HSP-70 binding domain allowing association with HSP-70. Therefore, disruption of the association using an AIF mutant lacking this domain can restore the potential of AIF importing into nucleus, and finally triggers cell death in a time dependent manner.
authors.affiliation: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing 400016, People's Republic of China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing 400016, People's Republic of China.
authors.forename: An-Ya
authors.initials: AY
authors.lastname: Dai
authors.affiliation: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing 400016, People's Republic of China.
authors.forename: Kun
authors.initials: K
authors.lastname: Tao
authors.affiliation: Department of Hematology, The First Affiliated Hospital, Chongqing Medical University, Chongqing 400016, People's Republic of China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing 400016, People's Republic of China.
authors.forename: Zheng-Lan
authors.initials: ZL
authors.lastname: Huang
authors.affiliation: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing 400016, People's Republic of China.
authors.forename: Miao
authors.initials: M
authors.lastname: Gao
authors.affiliation: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing 400016, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Hematology, The First Affiliated Hospital, Chongqing Medical University, Chongqing 400016, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing 400016, People's Republic of China.
authors.forename: Wei-Xi
authors.initials: WX
authors.lastname: Cao
authors.affiliation: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing 400016, People's Republic of China. Electronic address: fengwlcqmu@sina.com.
authors.forename: Wen-Li
authors.initials: WL
authors.lastname: Feng
mesh_terms: D021581:Active Transport, Cell Nucleus; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D018922:HL-60 Cells; D018840:HSP70 Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs
chemical_list: C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D018840:HSP70 Heat-Shock Proteins; D016044:Fusion Proteins, bcr-abl
keywords: Apoptosis; Apoptosis-inducing factor (AIF); Bcr/Abl fusion protein; Chronic myeloid leukemia (CML); Heat shock protein-70 (HSP-70)