This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nachmias, B. Articles by Ben-Yehuda, D. Search for Related Content PubMed PubMed Citation Articles by Nachmias, B. Articles by Ben-Yehuda, D.

Caspase-Mediated Cleavage Converts Livin from an Antiapoptotic to a Proapoptotic Factor

Implications for Drug-Resistant Melanoma

Departments of Hematology [B. N., Y. A., V. B., D. B-Y.] and Oncology [O. D., L. K., M. L., T. P.], Hadassah University Hospital, and The Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School [O. M.], Jerusalem 91120, Israel

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.

This article has been cited by other articles:

				M. Lotem, A. Machlenkin, T. Hamburger, A. Nissan, L. Kadouri, S. Frankenburg, Z. Gimmon, O. Elias, I. B. David, A. Kuznetz, et al. Autologous Melanoma Vaccine Induces Antitumor and Self-Reactive Immune Responses That Affect Patient Survival and Depend on MHC Class II Expression on Vaccine Cells Clin. Cancer Res., August 1, 2009; 15(15): 4968 - 4977. [Abstract] [Full Text] [PDF]

				I. Abd-Elrahman, K. Hershko, T. Neuman, B. Nachmias, R. Perlman, and D. Ben-Yehuda The Inhibitor of Apoptosis Protein Livin (ML-IAP) Plays a Dual Role in Tumorigenicity Cancer Res., July 1, 2009; 69(13): 5475 - 5480. [Abstract] [Full Text] [PDF]

				L. Wang, Q. Zhang, B. Liu, M. Han, and B. Shan Challenge and promise: roles for Livin in progression and therapy of cancer Mol. Cancer Ther., December 1, 2008; 7(12): 3661 - 3669. [Abstract] [Full Text] [PDF]

				J. N. Dynek, S. M. Chan, J. Liu, J. Zha, W. J. Fairbrother, and D. Vucic Microphthalmia-Associated Transcription Factor Is a Critical Transcriptional Regulator of Melanoma Inhibitor of Apoptosis in Melanomas Cancer Res., May 1, 2008; 68(9): 3124 - 3132. [Abstract] [Full Text] [PDF]

				C.-H. Pui Livin: a proapoptotic factor in ALL? Blood, January 15, 2007; 109(2): 394 - 395. [Full Text] [PDF]

				J. Choi, Y. K. Hwang, K. W. Sung, S. H. Lee, K. H. Yoo, H. L. Jung, H. H. Koo, H.-J. Kim, H. J. Kang, H. Y. Shin, et al. Expression of Livin, an antiapoptotic protein, is an independent favorable prognostic factor in childhood acute lymphoblastic leukemia Blood, January 15, 2007; 109(2): 471 - 477. [Abstract] [Full Text] [PDF]

				H. Chang and A. D. Schimmer Livin/melanoma inhibitor of apoptosis protein as a potential therapeutic target for the treatment of malignancy Mol. Cancer Ther., January 1, 2007; 6(1): 24 - 30. [Abstract] [Full Text] [PDF]

				J. Silke, T. Kratina, D. Chu, P. G. Ekert, C. L. Day, M. Pakusch, D. C. S. Huang, and D. L. Vaux Determination of cell survival by RING-mediated regulation of inhibitor of apoptosis (IAP) protein abundance PNAS, November 8, 2005; 102(45): 16182 - 16187. [Abstract] [Full Text] [PDF]

				J Gong, N Chen, Q Zhou, B Yang, Y Wang, and X Wang Melanoma inhibitor of apoptosis protein is expressed differentially in melanoma and melanocytic naevus, but similarly in primary and metastatic melanomas J. Clin. Pathol., October 1, 2005; 58(10): 1081 - 1085. [Abstract] [Full Text] [PDF]

				H. Hariu, Y. Hirohashi, T. Torigoe, H. Asanuma, M. Hariu, Y. Tamura, K. Aketa, C. Nabeta, K. Nakanishi, K. Kamiguchi, et al. Aberrant Expression and Potency as a Cancer Immunotherapy Target of Inhibitor of Apoptosis Protein Family, Livin/ML-IAP in Lung Cancer Clin. Cancer Res., February 1, 2005; 11(3): 1000 - 1009. [Abstract] [Full Text] [PDF]