title: tLivin displays flexibility by promoting alternative cell death mechanisms.
abstract: Livin is a member of the Inhibitor of Apoptosis (IAP) protein family that inhibits apoptosis triggered by a variety of stimuli. We previously demonstrated that while Livin inhibits caspase activity, caspases can cleave Livin to produce a truncated protein, tLivin and that this newly formed tLivin paradoxically induces cell death. However to date, the mechanism of tLivin-induced cell death is not fully understood. In this study, we set out to characterize the form of cell death mediated by tLivin. Here we demonstrate that, unlike most death-promoting proteins, tLivin is a flexible inducer of cell death capable of promoting necrosis or apoptosis in different cell lines. The unusual flexibility of tLivin is displayed by its ability to activate an alternative form of cell death when apoptosis is inhibited. Thus, tLivin can promote more than one form of cell death in the same cell type. Interestingly, in cells where tLivin induces necrosis, deletion of the caspase binding BIR domain results in tLivin-induced apoptosis, suggesting the BIR domain can potentially hamper the ability of tLivin to induce apoptosis. We further elucidate that tLivin activates the JNK pathway and both tLivin-induced apoptosis and necrosis are partially mediated by JNK activity. Acquired resistance to apoptosis, common in many tumors, impinges on the efficiency of conventional anti-cancer agents that function primarily by inducing apoptosis. The ability of tLivin to induce death of apoptosis-compromised cells makes it an attractive candidate for targeted cancer therapy.
authors: Division of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Tamar
authors: T
authors: Shiloach
authors: Department of Biology/Microbiology, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, Erlangen, Germany.
authors: Christian
authors: C
authors: Berens
authors: Department of Biology/Microbiology, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, Erlangen, Germany.
authors: Christina
authors: C
authors: Danke
authors: Division of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Ortal
authors: O
authors: Waiskopf
authors: Division of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Riki
authors: R
authors: Perlman
authors: Division of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Dina
authors: D
authors: Ben-Yehuda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D002460:Cell Line; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D020935:MAP Kinase Signaling System; D009336:Necrosis / Q000378:metabolism; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C419866:BIRC7 protein, human; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D020169:Caspases