Caspase-mediated cleavage converts livin from an antiapoptotic to a proapoptotic factor: Implications for drug-resistant melanoma

Boaz Nachmias, Yaqoub Ashhab, Vered Bucholtz, Olga Drize, Luna Kadouri, Michal Lotem, Tamar Peretz, Ofer Mandelboim, Dina Ben-Yehuda*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

112 Scopus citations

Abstract

Inhibitor of apoptosis protein (IAP) is a family of intracellular proteins that plays an essential role in the regulation of apoptosis. Recently, we and others discovered a new member of this family, termed Livin. Many studies have focused on the inhibitory effect of IAPs on caspases. Here, we describe a novel regulatory mechanism by which Livin is cleaved by the caspases. Strikingly, the cleaved Livin, although containing intact baculovirus IAP repeat and RING domains, does not only lose its antiapoptotic function but also gains a proapoptotic effect. The cleavage is site specific at Asp-52 and is restricted to effector caspase-3 and -7. Most importantly, we demonstrate the role of Livin and this regulatory mechanism in the drug resistance of melanoma patients. Using primary cultures derived from melanoma patients, we found a correlation between Livin overexpression, in vitro drug resistance, and the patient's clinical response.

Original languageAmerican English
Pages (from-to)6340-6349
Number of pages10
JournalCancer Research
Volume63
Issue number19
StatePublished - 1 Oct 2003

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