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Science 4 April 1997:
Vol. 276. no. 5309, pp. 111 - 113
DOI: 10.1126/science.276.5309.111
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Reports

The Receptor for the Cytotoxic Ligand TRAIL

Guohua Pan, Karen O'Rourke, Arul M. Chinnaiyan, Reiner Gentz, Reinhard Ebner, Jian Ni, * Vishva M. Dixit *dagger

TRAIL (also known as Apo-2L) is a member of the tumor necrosis factor (TNF) ligand family that rapidly induces apoptosis in a variety of transformed cell lines. The human receptor for TRAIL was found to be an undescribed member of the TNF-receptor family (designated death receptor-4, DR4) that contains a cytoplasmic "death domain" capable of engaging the cell suicide apparatus but not the nuclear factor kappa B pathway in the system studied. Unlike Fas, TNFR-1, and DR3, DR4 could not use FADD to transmit the death signal, suggesting the use of distinct proximal signaling machinery. Thus, the DR4-TRAIL axis defines another receptor-ligand pair involved in regulating cell suicide and tissue homeostasis.

G. Pan, K. O'Rourke, A. M. Chinnaiyan, V. M. Dixit, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
R. Gentz, R. Ebner, J. Ni, Human Genome Sciences, 9410 Key West Avenue, Rockville, MD 20850-3338, USA.
*   These authors share senior authorship.

dagger    To whom correspondence should be addressed. E-mail: vmdixit{at}umich.edu

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Potent Anti-R5 Human Immunodeficiency Virus Type 1 Effects of a CCR5 Antagonist, AK602/ONO4128/GW873140, in a Novel Human Peripheral Blood Mononuclear Cell Nonobese Diabetic-SCID, Interleukin-2 Receptor {gamma}-Chain-Knocked-Out AIDS Mouse Model.
H. Nakata, K. Maeda, T. Miyakawa, S. Shibayama, M. Matsuo, Y. Takaoka, M. Ito, Y. Koyanagi, and H. Mitsuya (2005)
J. Virol. 79, 2087-2096
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Resistance to Apo2 Ligand (Apo2L)/Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-Mediated Apoptosis and Constitutive Expression of Apo2L/TRAIL in Human T-Cell Leukemia Virus Type 1-Infected T-Cell Lines.
T. Matsuda, A. Almasan, M. Tomita, J.-n. Uchihara, M. Masuda, K. Ohshiro, N. Takasu, H. Yagita, T. Ohta, and N. Mori (2005)
J. Virol. 79, 1367-1378
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Receptor-selective Mutants of Apoptosis-inducing Ligand 2/Tumor Necrosis Factor-related Apoptosis-inducing Ligand Reveal a Greater Contribution of Death Receptor (DR) 5 than DR4 to Apoptosis Signaling.
R. F. Kelley, K. Totpal, S. H. Lindstrom, M. Mathieu, K. Billeci, L. DeForge, R. Pai, S. G. Hymowitz, and A. Ashkenazi (2005)
J. Biol. Chem. 280, 2205-2212
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Fas-associated Protein with Death Domain (FADD)-independent Recruitment of c-FLIPL to Death Receptor 5.
T.-G. Jin, A. Kurakin, N. Benhaga, K. Abe, M. Mohseni, F. Sandra, K. Song, B. K. Kay, and R. Khosravi-Far (2004)
J. Biol. Chem. 279, 55594-55601
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Cyr61 Suppresses Growth of Human Endometrial Cancer Cells.
W. Chien, T. Kumagai, C. W. Miller, J. C. Desmond, J. M. Frank, J. W. Said, and H. P. Koeffler (2004)
J. Biol. Chem. 279, 53087-53096
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Partial Contribution of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)/TRAIL Receptor Pathway to Antitumor Effects of Interferon-{alpha}/5-Fluorouracil against Hepatocellular Carcinoma.
T. Yamamoto, H. Nagano, M. Sakon, H. Wada, H. Eguchi, M. Kondo, B. Damdinsuren, H. Ota, M. Nakamura, H. Wada, et al. (2004)
Clin. Cancer Res. 10, 7884-7895
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T cells support osteoclastogenesis in an in vitro model derived from human multiple myeloma bone disease: the role of the OPG/TRAIL interaction.
S. Colucci, G. Brunetti, R. Rizzi, A. Zonno, G. Mori, G. Colaianni, D. Del Prete, R. Faccio, A. Liso, S. Capalbo, et al. (2004)
Blood 104, 3722-3730
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Reduced Apoptosis and Ameliorated Listeriosis in TRAIL-Null Mice.
S.-J. Zheng, J. Jiang, H. Shen, and Y. H. Chen (2004)
J. Immunol. 173, 5652-5658
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Sodium butyrate sensitizes TRAIL-mediated apoptosis by induction of transcription from the DR5 gene promoter through Sp1 sites in colon cancer cells.
Y.-H. Kim, J.-W. Park, J.-Y. Lee, and T. K. Kwon (2004)
Carcinogenesis 25, 1813-1820
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Concentration of osteoprotegerin (OPG) in peritoneal fluid is increased in women with endometriosis.
M. Harada, Y. Osuga, T. Hirata, Y. Hirota, K. Koga, O. Yoshino, C. Morimoto, T. Fujiwara, M. Momoeda, T. Yano, et al. (2004)
Hum. Reprod. 19, 2188-2191
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Death Induction by Recombinant Native TRAIL and Its Prevention by a Caspase 9 Inhibitor in Primary Human Esophageal Epithelial Cells.
S.-H. Kim, K. Kim, J. G. Kwagh, D. T. Dicker, M. Herlyn, A. K. Rustgi, Y. Chen, and W. S. El-Deiry (2004)
J. Biol. Chem. 279, 40044-40052
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Inducible Silencing of KILLER/DR5 In vivo Promotes Bioluminescent Colon Tumor Xenograft Growth and Confers Resistance to Chemotherapeutic Agent 5-Fluorouracil.
S. Wang and W. S. El-Deiry (2004)
Cancer Res. 64, 6666-6672
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Deficient Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Death Receptor Transport to the Cell Surface in Human Colon Cancer Cells Selected for Resistance to TRAIL-induced Apoptosis.
Z. Jin, E. R. McDonald III, D. T. Dicker, and W. S. El-Deiry (2004)
J. Biol. Chem. 279, 35829-35839
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Apo2 Ligand/Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Cooperates with Chemotherapy to Inhibit Orthotopic Lung Tumor Growth and Improve Survival.
H. Jin, R. Yang, S. Fong, K. Totpal, D. Lawrence, Z. Zheng, J. Ross, H. Koeppen, R. Schwall, and A. Ashkenazi (2004)
Cancer Res. 64, 4900-4905
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Down-regulation of protein kinase C{eta} potentiates the cytotoxic effects of exogenous tumor necrosis factor-related apoptosis-inducing ligand in PC-3 prostate cancer cells.
J. Sonnemann, V. Gekeler, A. Sagrauske, C. Muller, H.-P. Hofmann, and J. F. Beck (2004)
Mol. Cancer Ther. 3, 773-781
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TNF-related apoptosis-inducing ligand is involved in neutropenia of systemic lupus erythematosus.
W. Matsuyama, M. Yamamoto, I. Higashimoto, K.-i. Oonakahara, M. Watanabe, K. Machida, T. Yoshimura, N. Eiraku, M. Kawabata, M. Osame, et al. (2004)
Blood 104, 184-191
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Proteolysis of the Mismatch Repair Protein MLH1 by Caspase-3 Promotes DNA Damage-induced Apoptosis.
F. Chen, O. K. Arseven, and V. L. Cryns (2004)
J. Biol. Chem. 279, 27542-27548
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Inflammatory Cytokines and Postmyocardial Infarction Remodeling.
M. Nian, P. Lee, N. Khaper, and P. Liu (2004)
Circ. Res. 94, 1543-1553
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Tissue Distribution of the Death Ligand TRAIL and Its Receptors.
D. C. Spierings, E. G. de Vries, E. Vellenga, F. A. van den Heuvel, J. J. Koornstra, J. Wesseling, H. Hollema, and S. de Jong (2004)
J. Histochem. Cytochem. 52, 821-831
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`The stress of dying': the role of heat shock proteins in the regulation of apoptosis.
H. M. Beere (2004)
J. Cell Sci. 117, 2641-2651
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Graft-versus-leukemia in a retrovirally induced murine CML model: mechanisms of T-cell killing.
C. C. Matte, J. Cormier, B. E. Anderson, I. Athanasiadis, J. Liu, S. G. Emerson, W. Pear, and W. D. Shlomchik (2004)
Blood 103, 4353-4361
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Uveal Melanoma Expression of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) Receptors and Susceptibility to TRAIL-Induced Apoptosis.
D. H. Ren, E. Mayhew, C. Hay, H. Li, H. Alizadeh, and J. Y. Niederkorn (2004)
Invest. Ophthalmol. Vis. Sci. 45, 1162-1168
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Xenopus Death Receptor-M1 and -M2, New Members of the Tumor Necrosis Factor Receptor Superfamily, Trigger Apoptotic Signaling by Differential Mechanisms.
K. Tamura, T. Noyama, Y.-h. Ishizawa, N. Takamatsu, T. Shiba, and M. Ito (2004)
J. Biol. Chem. 279, 7629-7635
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Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Decoy Receptor TRAIL-R3 Is Up-regulated by p53 in Breast Tumor Cells through a Mechanism Involving an Intronic p53-binding Site.
C. R. de Almodovar, C. Ruiz-Ruiz, A. Rodriguez, G. Ortiz-Ferron, J. M. Redondo, and A. Lopez-Rivas (2004)
J. Biol. Chem. 279, 4093-4101
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Characterization of tumour necrosis factor-{alpha}-related apoptosis-inducing ligand and its receptors in the adult human testis.
R. Grataroli, D. Vindrieux, J. Selva, C. Felsenheld, A. Ruffion, M. Decaussin, and M. Benahmed (2004)
Mol. Hum. Reprod. 10, 123-128
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Neutrophil-Derived TNF-Related Apoptosis-Inducing Ligand (TRAIL): A Novel Mechanism of Antitumor Effect by Neutrophils.
Y. Koga, A. Matsuzaki, A. Suminoe, H. Hattori, and T. Hara (2004)
Cancer Res. 64, 1037-1043
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Interleukin-1{beta} and Tumor Necrosis Factor (TNF)-{alpha} Sensitize Human Thyroid Epithelial Cells to TNF-Related Apoptosis-Inducing Ligand-Induced Apoptosis through Increases in Procaspase-7 and Bid, and the Down-Regulation of p44/42 Mitogen-Activated Protein Kinase Activity.
E. Mezosi, S. H. Wang, S. Utsugi, L. Bajnok, J. D. Bretz, P. G. Gauger, N. W. Thompson, and J. R. Baker Jr. (2004)
J. Clin. Endocrinol. Metab. 89, 250-257
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