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The Inhibitor of Apoptosis Protein Livin (ML-IAP) Plays a Dual Role in Tumorigenicity

¹ Division of Hematology and ² Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Requests for reprints: Dina Ben-Yehuda, Division of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel. Phone: 972-2-6776744/8; Fax: 972-2-6423067; E-mail: dbyehuda{at}hadassah.org.il.

Key Words: Inhibitor of apoptosis protein • tumor development • NK cells

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 and β, 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 and β on the initiation and development of tumors were compared. In the animal model, Livin promotes tumor initiation in comparison with control. Interestingly, the growth of tumors originating from cells expressing Livin β was inhibited. In these tumors, Livin β was cleaved and produced a high level of the proapoptotic tLivin β that repressed tumor development. When we eliminated the proapoptotic effect of Livin β by point mutations, the resulting antiapoptotic Livin β mutants contributed to tumor progression. In terms of mechanism, we show that Livin β 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. [Cancer Res 2009;69(13):5475–80]