Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

J. Biol. Chem. 276 (5): 3238-3246

© 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

Livin, a Novel Inhibitor of Apoptosis Protein Family Member*

Gary M. Kasof and Bruce C. GomesDagger

From AstraZeneca Pharmaceuticals, Enabling Sciences and Technology, Wilmington, Delaware 19803

A novel human inhibitor of apoptosis protein (IAP) family member termed Livin was identified, containing a single baculoviral IAP repeat (BIR) domain and a COOH-terminal RING finger domain. The mRNA for livin was not detectable by Northern blot in most normal adult tissues with the exception of the placenta, but was present in developmental tissues and in several cancer cell lines. Highest levels were observed in two melanoma-derived cell lines, G361 and SK-Mel29. Transfection of livin in HeLa cells resulted in protection from apoptosis induced by expression of FADD, Bax, RIP, RIP3, and DR6. Similar to other IAP family members, the anti-apoptotic activity of Livin was dependent on the BIR domain. Livin was also capable of inhibiting DEVD-like caspase activity triggered by tumor necrosis factor-alpha . In vitro binding studies demonstrated a direct interaction between Livin and the active form of the downstream caspases, caspase-3 and -7, that was dependent on the BIR domain of Livin. In addition, the unprocessed and cleaved forms of caspase-9 co-immunoprecipitated with Livin in vivo, and recombinant Livin could inhibit the activation of caspase-9 induced by Apaf-1, cytochrome c, and dATP. The subcellular distribution of the transfected Livin was analyzed by immunofluorescence. Both Livin and Survivin were expressed in the nucleus and in a filamentous pattern throughout the cytoplasm. In contrast to the apoptotic activity, the COOH-terminal RING domain mediated its subcellular localization patterning. Further studies found that transfection of an antisense construct against livin could trigger apoptosis specifically in cell lines expressing livin mRNA. This was associated with an increase in DNA fragmentation and in DEVD-like caspase activity. Thus, disruption of Livin may provide a strategy to induce apoptosis in certain cancer cells.


* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: AstraZeneca Pharmaceuticals, Enabling Science and Technology, CRDL 145, 1800 Concord Pike, Wilmington, DE 19803. Tel.: 302-886-8043; Fax: 302-886-8830; E-mail: bruce.gomes@astrazeneca.com.


Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
cIAP1 Cooperatively Inhibits Procaspase-3 Activation by the Caspase-9 Apoptosome.
S. P. Burke, L. Smith, and J. B. Smith (2010)
J. Biol. Chem. 285, 30061-30068
   Abstract »    Full Text »    PDF »
Survivin and Smac Gene Expressions but not Livin Are Predictors of Prognosis in Non-small Cell Lung Cancer Patients Treated with Adjuvant Chemotherapy Following Surgery.
C. H. Dai, J. Li, S. B. Shi, L. C. Yu, L. P. Ge, and P. Chen (2010)
Jpn. J. Clin. Oncol. 40, 327-335
   Abstract »    Full Text »    PDF »
Therapeutic potential of siRNA-mediated combined knockdown of the IAP genes (Livin, XIAP, and Survivin) on human bladder cancer T24 cells.
D. Yang, X. Song, J. Zhang, L. Ye, S. Wang, X. Che, J. Wang, Z. Zhang, L. Wang, and W. Shi (2010)
Acta Biochim Biophys Sin 42, 137-144
   Abstract »    Full Text »    PDF »
The Oncolytic Activity of Newcastle Disease Virus NDV-HUJ on Chemoresistant Primary Melanoma Cells Is Dependent on the Proapoptotic Activity of the Inhibitor of Apoptosis Protein Livin.
I. Lazar, B. Yaacov, T. Shiloach, E. Eliahoo, L. Kadouri, M. Lotem, R. Perlman, Z. Zakay-Rones, A. Panet, and D. Ben-Yehuda (2010)
J. Virol. 84, 639-646
   Abstract »    Full Text »    PDF »
The Inhibitor of Apoptosis Protein Livin (ML-IAP) Plays a Dual Role in Tumorigenicity.
I. Abd-Elrahman, K. Hershko, T. Neuman, B. Nachmias, R. Perlman, and D. Ben-Yehuda (2009)
Cancer Res. 69, 5475-5480
   Abstract »    Full Text »    PDF »
Challenge and promise: roles for Livin in progression and therapy of cancer.
L. Wang, Q. Zhang, B. Liu, M. Han, and B. Shan (2008)
Mol. Cancer Ther. 7, 3661-3669
   Abstract »    Full Text »    PDF »
Microphthalmia-Associated Transcription Factor Is a Critical Transcriptional Regulator of Melanoma Inhibitor of Apoptosis in Melanomas.
J. N. Dynek, S. M. Chan, J. Liu, J. Zha, W. J. Fairbrother, and D. Vucic (2008)
Cancer Res. 68, 3124-3132
   Abstract »    Full Text »    PDF »
Small Molecules Destabilize cIAP1 by Activating Auto-ubiquitylation.
K. Sekine, K. Takubo, R. Kikuchi, M. Nishimoto, M. Kitagawa, F. Abe, K. Nishikawa, T. Tsuruo, and M. Naito (2008)
J. Biol. Chem. 283, 8961-8968
   Abstract »    Full Text »    PDF »
Expression of Livin, an antiapoptotic protein, is an independent favorable prognostic factor in childhood acute lymphoblastic leukemia.
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. (2007)
Blood 109, 471-477
   Abstract »    Full Text »    PDF »
Livin/melanoma inhibitor of apoptosis protein as a potential therapeutic target for the treatment of malignancy.
H. Chang and A. D. Schimmer (2007)
Mol. Cancer Ther. 6, 24-30
   Abstract »    Full Text »    PDF »
Survivin Expression Is Regulated by Coexpression of Human Epidermal Growth Factor Receptor 2 and Epidermal Growth Factor Receptor via Phosphatidylinositol 3-Kinase/AKT Signaling Pathway in Breast Cancer Cells.
H. Asanuma, T. Torigoe, K. Kamiguchi, Y. Hirohashi, T. Ohmura, K. Hirata, M. Sato, and N. Sato (2005)
Cancer Res. 65, 11018-11025
   Abstract »    Full Text »    PDF »
Determination of cell survival by RING-mediated regulation of inhibitor of apoptosis (IAP) protein abundance.
J. Silke, T. Kratina, D. Chu, P. G. Ekert, C. L. Day, M. Pakusch, D. C. S. Huang, and D. L. Vaux (2005)
PNAS 102, 16182-16187
   Abstract »    Full Text »    PDF »
X-Linked Inhibitor of Apoptosis Protein Expression Level in Colorectal Cancer Is Regulated by Hepatocyte Growth Factor/C-Met Pathway via Akt Signaling.
H. Takeuchi, J. Kim, A. Fujimoto, N. Umetani, T. Mori, A. Bilchik, R. Turner, A. Tran, C. Kuo, and D. S.B. Hoon (2005)
Clin. Cancer Res. 11, 7621-7628
   Abstract »    Full Text »    PDF »
Melanoma inhibitor of apoptosis protein is expressed differentially in melanoma and melanocytic naevus, but similarly in primary and metastatic melanomas.
J Gong, N Chen, Q Zhou, B Yang, Y Wang, and X Wang (2005)
J. Clin. Pathol. 58, 1081-1085
   Abstract »    Full Text »    PDF »
Regulation of Vein Graft Hyperplasia by Survivin, an Inhibitor of Apoptosis Protein.
G. J. Wang, X. X. Sui, H. F. Simosa, M. K. Jain, D. C. Altieri, and M. S. Conte (2005)
Arterioscler Thromb Vasc Biol 25, 2081-2087
   Abstract »    Full Text »    PDF »
Expression of Smac/DIABLO in mouse preimplantation embryos and its correlation to apoptosis and fragmentation.
Y. Honda, H. Tanikawa, J. Fukuda, K. Kawamura, N. Sato, T. Sato, Y. Shimizu, H. Kodama, and T. Tanaka (2005)
Mol. Hum. Reprod. 11, 183-188
   Abstract »    Full Text »    PDF »
Apoptosis in the development and treatment of cancer.
R. Gerl and D. L. Vaux (2005)
Carcinogenesis 26, 263-270
   Abstract »    Full Text »    PDF »
Aberrant Expression and Potency as a Cancer Immunotherapy Target of Inhibitor of Apoptosis Protein Family, Livin/ML-IAP in Lung Cancer.
H. Hariu, Y. Hirohashi, T. Torigoe, H. Asanuma, M. Hariu, Y. Tamura, K. Aketa, C. Nabeta, K. Nakanishi, K. Kamiguchi, et al. (2005)
Clin. Cancer Res. 11, 1000-1009
   Abstract »    Full Text »    PDF »
Cellular, Biochemical, and Genetic Analysis of Mechanism of Small Molecule IAP Inhibitors.
Z. Wang, M. Cuddy, T. Samuel, K. Welsh, A. Schimmer, F. Hanaii, R. Houghten, C. Pinilla, and J. C. Reed (2004)
J. Biol. Chem. 279, 48168-48176
   Abstract »    Full Text »    PDF »
CC Chemokine Ligand 25 Enhances Resistance to Apoptosis in CD4+ T Cells from Patients with T-Cell Lineage Acute and Chronic Lymphocytic Leukemia by Means of Livin Activation.
Z. Qiuping, X. Jei, J. Youxin, J. Wei, L. Chun, W. Jin, W. Qun, L. Yan, H. Chunsong, Y. Mingzhen, et al. (2004)
Cancer Res. 64, 7579-7587
   Abstract »    Full Text »    PDF »
Neuronal Apoptosis-inhibitory Protein Does Not Interact with Smac and Requires ATP to Bind Caspase-9.
J. Davoodi, L. Lin, J. Kelly, P. Liston, and A. E. MacKenzie (2004)
J. Biol. Chem. 279, 40622-40628
   Abstract »    Full Text »    PDF »
Telomere-based DNA damage responses: a new approach to melanoma.
N. PURI, M. S. ELLER, H. R. BYERS, S. DYKSTRA, J. KUBERA, and B. A. GILCHREST (2004)
FASEB J 18, 1373-1381
   Abstract »    Full Text »    PDF »
Caspase-dependent cytochrome c release and cell death in chick cardiomyocytes after simulated ischemia-reperfusion.
Y. Qin, T. L. Vanden Hoek, K. Wojcik, T. Anderson, C.-Q. Li, Z.-H. Shao, L. B. Becker, and K. J. Hamann (2004)
Am J Physiol Heart Circ Physiol 286, H2280-H2286
   Abstract »    Full Text »    PDF »
Survivin Enhances Fas Ligand Expression via Up-Regulation of Specificity Protein 1-Mediated Gene Transcription in Colon Cancer Cells.
K. Asanuma, N. Tsuji, T. Endoh, A. Yagihashi, and N. Watanabe (2004)
J. Immunol. 172, 3922-3929
   Abstract »    Full Text »    PDF »
Essential Role of Survivin, an Inhibitor of Apoptosis Protein, in T Cell Development, Maturation, and Homeostasis.
Z. Xing, E. M. Conway, C. Kang, and A. Winoto (2004)
J. Exp. Med. 199, 69-80
   Abstract »    Full Text »    PDF »
Classification of pediatric acute lymphoblastic leukemia by gene expression profiling.
M. E. Ross, X. Zhou, G. Song, S. A. Shurtleff, K. Girtman, W. K. Williams, H.-C. Liu, R. Mahfouz, S. C. Raimondi, N. Lenny, et al. (2003)
Blood 102, 2951-2959
   Abstract »    Full Text »    PDF »
Caspase-Mediated Cleavage Converts Livin from an Antiapoptotic to a Proapoptotic Factor: Implications for Drug-Resistant Melanoma.
B. Nachmias, Y. Ashhab, V. Bucholtz, O. Drize, L. Kadouri, M. Lotem, T. Peretz, O. Mandelboim, and D. Ben-Yehuda (2003)
Cancer Res. 63, 6340-6349
   Abstract »    Full Text »    PDF »
Detection of Anti-Livin Antibody in Gastrointestinal Cancer Patients.
A. Yagihashi, K. Asanuma, N. Tsuji, T. Torigoe, N. Sato, K. Hirata, and N. Watanabe (2003)
Clin. Chem. 49, 1206-1208
   Full Text »    PDF »
Direct Interaction between Survivin and Smac/DIABLO Is Essential for the Anti-apoptotic Activity of Survivin during Taxol-induced Apoptosis.
Z. Song, X. Yao, and M. Wu (2003)
J. Biol. Chem. 278, 23130-23140
   Abstract »    Full Text »    PDF »
Melanoma inhibitor of apoptosis protein (ML-IAP) is a target for immune-mediated tumor destruction.
J. C. Schmollinger, R. H. Vonderheide, K. M. Hoar, B. Maecker, J. L. Schultze, F. S. Hodi, R. J. Soiffer, K. Jung, M. J. Kuroda, N. L. Letvin, et al. (2003)
PNAS 100, 3398-3403
   Abstract »    Full Text »    PDF »
Role and Gonadotrophic Regulation of X-Linked Inhibitor of Apoptosis Protein Expression During Rat Ovarian Follicular Development In Vitro.
Y. Wang, P. U. Rippstein, and B. K. Tsang (2003)
Biol Reprod 68, 610-619
   Abstract »    Full Text »    PDF »
DNA Damage Induces a Novel p53-Survivin Signaling Pathway Regulating Cell Cycle and Apoptosis in Acute Lymphoblastic Leukemia Cells.
M. Zhou, L. Gu, F. Li, Y. Zhu, W. G. Woods, and H. W. Findley (2002)
J. Pharmacol. Exp. Ther. 303, 124-131
   Abstract »    Full Text »    PDF »
The antiapoptosis protein survivin is associated with cell cycle entry of normal cord blood CD34+ cells and modulates cell cycle and proliferation of mouse hematopoietic progenitor cells.
S. Fukuda, R. G. Foster, S. B. Porter, and L. M. Pelus (2002)
Blood 100, 2463-2471
   Abstract »    Full Text »    PDF »
ILPIP, a Novel Anti-apoptotic Protein That Enhances XIAP-mediated Activation of JNK1 and Protection against Apoptosis.
M. G. Sanna, J. da Silva Correia, Y. Luo, B. Chuang, L. M. Paulson, B. Nguyen, Q. L. Deveraux, and R. J. Ulevitch (2002)
J. Biol. Chem. 277, 30454-30462
   Abstract »    Full Text »    PDF »
Apoptosis: Target of Cancer Therapy.
C. G. Ferreira, M. Epping, F. A. E. Kruyt, and G. Giaccone (2002)
Clin. Cancer Res. 8, 2024-2034
   Abstract »    Full Text »    PDF »
Involvement of Transforming Growth Factor {alpha} in the Regulation of Rat Ovarian X-Linked Inhibitor of Apoptosis Protein Expression and Follicular Growth by Follicle-Stimulating Hormone.
Y. Wang, E. Asselin, and B. K. Tsang (2002)
Biol Reprod 66, 1672-1680
   Abstract »    Full Text »    PDF »
Bcl-2 and Bcl-xL Inhibit CD95-mediated Apoptosis by Preventing Mitochondrial Release of Smac/DIABLO and Subsequent Inactivation of X-linked Inhibitor-of-Apoptosis Protein.
X.-M. Sun, S. B. Bratton, M. Butterworth, M. MacFarlane, and G. M. Cohen (2002)
J. Biol. Chem. 277, 11345-11351
   Abstract »    Full Text »    PDF »
IAP Suppression of Apoptosis Involves Distinct Mechanisms: the TAK1/JNK1 Signaling Cascade and Caspase Inhibition.
M. G. Sanna, J. d. S. Correia, O. Ducrey, J. Lee, K. Nomoto, N. Schrantz, Q. L. Deveraux, and R. J. Ulevitch (2002)
Mol. Cell. Biol. 22, 1754-1766
   Abstract »    Full Text »    PDF »
The loss of IAP expression during HL-60 cell differentiation is caspase-independent.
B. T. Doyle, A. J. O'Neill, P. Newsholme, J. M. Fitzpatrick, and R. W. G. Watson (2002)
J. Leukoc. Biol. 71, 247-254
   Abstract »    Full Text »    PDF »
Cellular stress response and apoptosis in cancer therapy.
I. Herr and K.-M. Debatin (2001)
Blood 98, 2603-2614
   Abstract »    Full Text »    PDF »
Characterization of XIAP-Deficient Mice.
H. Harlin, S. B. Reffey, C. S. Duckett, T. Lindsten, and C. B. Thompson (2001)
Mol. Cell. Biol. 21, 3604-3608
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882