The inhibitor of apoptosis protein Livin (ML-IAP) plays a dual role in tumorigenicity.
The inhibitor of apoptosis protein (IAP) family can inhibit apoptosis induced by a variety of stimuli. We and others previously described the IAP Livin (ML-IAP). We found that Livin is unique among the IAP members as, on a strong apoptotic stimulus, it is specifically cleaved by caspases to produce a truncated protein with paradoxical proapoptotic activity (tLivin). We also showed that Livin encodes two splicing variants, termed Livin alpha and beta, with diverse antiapoptotic effects in vitro. In this study, we compared the Livin isoforms in vivo. An animal model was established and the effects of Livin alpha and beta on the initiation and development of tumors were compared. In the animal model, Livin alpha promotes tumor initiation in comparison with control. Interestingly, the growth of tumors originating from cells expressing Livin beta was inhibited. In these tumors, Livin beta was cleaved and produced a high level of the proapoptotic tLivin beta that repressed tumor development. When we eliminated the proapoptotic effect of Livin beta by point mutations, the resulting antiapoptotic Livin beta mutants contributed to tumor progression. In terms of mechanism, we show that Livin beta tumors develop only in mice lacking natural killer (NK) cell activity. Thus, from the animal model, we can conclude that Livin plays a major role in tumorigenicity and that NK cells induce cleavage of Livin to its proapoptotic truncated protein that in turn inhibits tumor growth. Therefore, Livin and tLivin may serve as potential targets for cancer therapy.
Abd-Elrahman
Ihab
I
Division of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Hershko
Klilah
K
Neuman
Tzahi
T
Nachmias
Boaz
B
Perlman
Riki
R
Ben-Yehuda
Dina
D
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D018450:Disease Progression; D014644:Genetic Variation; D005822:Genetic Vectors; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D009369:Neoplasms / Q000473:pathology; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; C419866:BIRC7 protein, human; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; C000607735:livin protein, mouse