Shiloach Tamar, Berens Christian, Danke Christina, Waiskopf Ortal, Perlman Riki, Ben-Yehuda Dina
Division of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Department of Biology/Microbiology, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, Erlangen, Germany.
PLoS One. 2014 Jun 24;9(6):e101075. doi: 10.1371/journal.pone.0101075. eCollection 2014.
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.
Livin是凋亡抑制蛋白（IAP）家族的成员，可抑制多种刺激引发的细胞凋亡。我们之前证实，虽然Livin抑制半胱天冬酶活性，但半胱天冬酶可切割Livin以产生截短蛋白tLivin，而这种新形成的tLivin却反常地诱导细胞死亡。然而，迄今为止，tLivin诱导细胞死亡的机制尚未完全明确。在本研究中，我们着手对tLivin介导的细胞死亡形式进行特征描述。在此我们证明，与大多数促死亡蛋白不同，tLivin是一种灵活的细胞死亡诱导剂，能够在不同细胞系中促进坏死或凋亡。tLivin的异常灵活性表现为当凋亡受到抑制时，它能够激活另一种细胞死亡形式。因此，tLivin可在同一细胞类型中促进不止一种细胞死亡形式。有趣的是，在tLivin诱导坏死的细胞中，删除半胱天冬酶结合BIR结构域会导致tLivin诱导凋亡，这表明BIR结构域可能会阻碍tLivin诱导凋亡的能力。我们进一步阐明，tLivin激活JNK通路，且tLivin诱导的凋亡和坏死均部分由JNK活性介导。对凋亡产生获得性抗性在许多肿瘤中很常见，这会影响主要通过诱导凋亡发挥作用的传统抗癌药物的疗效。tLivin诱导凋亡受损细胞死亡的能力使其成为靶向癌症治疗的一个有吸引力的候选药物。
