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Science 296 (5573): 1635-1636

Copyright © 2002 by the American Association for the Advancement of Science

The Fas Signaling Pathway: More Than a Paradigm

Harald Wajant

Apoptosis and related forms of cell death have central importance in development, homeostasis, tumor surveillance, and the function of the immune system. Apoptosis is initiated by two principal pathways. The intrinsic pathway emerges from mitochondria, whereas the extrinsic pathway is activated by the ligation of death receptors. This Viewpoint introduces the basic mechanisms of the extrinsic pathway, using the example of the prototypical death receptor Fas and its role in apoptosis, but it also points out the increasingly understood importance of this receptor as a non-apoptotic signal transducer.

Institute of Cell Biology and Immunology, Allmandring 31, University of Stuttgart, 70 569 Stuttgart, Germany. E-mail: harald.wajant{at}

Sertraline, an Antidepressant, Induces Apoptosis in Hepatic Cells Through the Mitogen-Activated Protein Kinase Pathway.
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Toxicol. Sci. 137, 404-415
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Complement Activation by Ceramide Transporter Proteins.
G. H. Bode, M. Losen, W. A. Buurman, R. Veerhuis, P. C. Molenaar, H. W. M. Steinbusch, M. H. De Baets, M. R. Daha, and P. Martinez-Martinez (2014)
J. Immunol. 192, 1154-1161
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Mechanical ventilation-induced apoptosis in newborn rat lung is mediated via FasL/Fas pathway.
A. A. Kroon, V. DelRiccio, I. Tseu, B. P. Kavanagh, and M. Post (2013)
Am J Physiol Lung Cell Mol Physiol 305, L795-L804
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Kupffer cells potentiate liver sinusoidal endothelial cell injury in sepsis by ligating programmed cell death ligand-1.
N. A. Hutchins, F. Wang, Y. Wang, C.-S. Chung, and A. Ayala (2013)
J. Leukoc. Biol. 94, 963-970
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New Insights into the Mechanisms of Ram Sperm Protection by Seminal Plasma Proteins.
N. Mendoza, A. Casao, R. Perez-Pe, J. A. Cebrian-Perez, and T. Muino-Blanco (2013)
Biol Reprod 88, 149
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Mitochondrial Control of Cellular Life, Stress, and Death.
L. Galluzzi, O. Kepp, C. Trojel-Hansen, and G. Kroemer (2012)
Circ. Res. 111, 1198-1207
   Abstract »    Full Text »    PDF »
Non-apoptotic functions of apoptosis-regulatory proteins.
L. Galluzzi, O. Kepp, C. Trojel-Hansen, and G. Kroemer (2012)
EMBO Rep. 13, 322-330
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Human cell-death-inducing DFF45-like effector C induces apoptosis via caspase-8.
X. Tang, Z. Xing, H. Tang, L. Liang, and M. Zhao (2011)
Acta Biochim Biophys Sin 43, 779-786
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FAM129B/MINERVA, a Novel Adherens Junction-associated Protein, Suppresses Apoptosis in HeLa Cells.
S. Chen, H. G. Evans, and D. R. Evans (2011)
J. Biol. Chem. 286, 10201-10209
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Apoptosis in Mouse Amniotic Epithelium Is Induced by Activated Macrophages Through the TNF Receptor Type 1/TNF Pathway.
K. Kobayashi, K. Umezawa, and M. Yasui (2011)
Biol Reprod 84, 248-254
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HDMX regulates p53 activity and confers chemoresistance to 3-Bis(2-chloroethyl)-1-nitrosourea.
G. Jin, S. Cook, B. Cui, W. C. Chen, S. T. Keir, P. Killela, C. Di, C. A. Payne, S. G. Gregory, R. McLendon, et al. (2010)
Neuro Oncology 12, 956-966
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Complex I deficiency due to loss of Ndufs4 in the brain results in progressive encephalopathy resembling Leigh syndrome.
A. Quintana, S. E. Kruse, R. P. Kapur, E. Sanz, and R. D. Palmiter (2010)
PNAS 107, 10996-11001
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Cisplatin Augments FAS-mediated Apoptosis through Lipid Rafts.
C.-R. HUANG, Z.-X. JIN, L. DONG, X.-P. TONG, S. YUE, T. KAWANAMI, T. SAWAKI, T. SAKAI, M. MIKI, H. IWAO, et al. (2010)
Anticancer Res 30, 2065-2071
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Fas/Fas Ligand-mediated Apoptosis in Different Cell Lineages and Functional Compartments of Human Lymph Nodes.
T. S. Kokkonen and T. J. Karttunen (2010)
Journal of Histochemistry & Cytochemistry 58, 131-140
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The Full-Length Isoform of Human Papillomavirus 16 E6 and Its Splice Variant E6* Bind to Different Sites on the Procaspase 8 Death Effector Domain.
S. S. Tungteakkhun, M. Filippova, N. Fodor, and P. J. Duerksen-Hughes (2010)
J. Virol. 84, 1453-1463
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Apoptotic Signalling in HeLa Hep2 Cells Following 5 Gy of Cobalt-60 Gamma Radiation.
Anticancer Res 29, 4361-4366
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Regulation of Fas-mediated immune homeostasis by an activation-induced protein, Cyclon.
S. Saint Fleur, A. Hoshino, K. Kondo, T. Egawa, and H. Fujii (2009)
Blood 114, 1355-1365
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Poly(ADP-ribose) polymerase suppression protects rheumatoid synovial fibroblasts from Fas-induced apoptosis.
S. Garcia, A. Mera, J. J. Gomez-Reino, and C. Conde (2009)
Rheumatology 48, 483-489
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Bcl-2 Inhibitors: Targeting Mitochondrial Apoptotic Pathways in Cancer Therapy.
M. H. Kang and C. P. Reynolds (2009)
Clin. Cancer Res. 15, 1126-1132
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Redox amplification of apoptosis by caspase-dependent cleavage of glutaredoxin 1 and S-glutathionylation of Fas.
V. Anathy, S. W. Aesif, A. S. Guala, M. Havermans, N. L. Reynaert, Y.-S. Ho, R. C. Budd, and Y. M.W. Janssen-Heininger (2009)
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Functional genetic screening reveals the role of mitochondrial cytochrome b as a mediator of FAS-induced apoptosis.
A. P. Komarov, O. W. Rokhlin, C.-A. Yu, and A. V. Gudkov (2008)
PNAS 105, 14453-14458
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Review Paper: Pathophysiology of Myocardial Reperfusion Injury: The Role of Genetically Engineered Mouse Models.
A. Ramachandran, S. Jha, and D. J. Lefer (2008)
Veterinary Pathology 45, 698-706
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DNA Mismatch Repair-dependent Activation of c-Abl/p73{alpha}/GADD45{alpha}-mediated Apoptosis.
L. S. Li, J. C. Morales, A. Hwang, M. W. Wagner, and D. A. Boothman (2008)
J. Biol. Chem. 283, 21394-21403
   Abstract »    Full Text »    PDF »
Fas Ag-FasL coupling leads to ERK1/2-mediated proliferation of gastric mucosal cells.
H. Li, X. Cai, X. Fan, B. Moquin, C. Stoicov, and J. Houghton (2008)
Am J Physiol Gastrointest Liver Physiol 294, G263-G275
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Evasion of myofibroblasts from immune surveillance: A mechanism for tissue fibrosis.
S. B. Wallach-Dayan, R. Golan-Gerstl, and R. Breuer (2007)
PNAS 104, 20460-20465
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Mitofusin 2 Triggers Vascular Smooth Muscle Cell Apoptosis via Mitochondrial Death Pathway.
X. Guo, K.-H. Chen, Y. Guo, H. Liao, J. Tang, and R.-P. Xiao (2007)
Circ. Res. 101, 1113-1122
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Blockade of Tumor Necrosis Factor-induced Bid Cleavage by Caspase-resistant Rb.
X. Huang, A. Masselli, S. M. Frisch, I. C. Hunton, Y. Jiang, and J. Y. J. Wang (2007)
J. Biol. Chem. 282, 29401-29413
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Mitofusin-2 Is a Major Determinant of Oxidative Stress-mediated Heart Muscle Cell Apoptosis.
T. Shen, M. Zheng, C. Cao, C. Chen, J. Tang, W. Zhang, H. Cheng, K.-H. Chen, and R.-P. Xiao (2007)
J. Biol. Chem. 282, 23354-23361
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High Expression Rates of Human Islet Amyloid Polypeptide Induce Endoplasmic Reticulum Stress Mediated {beta}-Cell Apoptosis, a Characteristic of Humans With Type 2 but Not Type 1 Diabetes.
C.-j. Huang, C.-y. Lin, L. Haataja, T. Gurlo, A. E. Butler, R. A. Rizza, and P. C. Butler (2007)
Diabetes 56, 2016-2027
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A Novel Epidermal Growth Factor Receptor Inhibitor Promotes Apoptosis in Non-Small Cell Lung Cancer Cells Resistant to Erlotinib.
T. de La Motte Rouge, L. Galluzzi, K. A. Olaussen, Y. Zermati, E. Tasdemir, T. Robert, H. Ripoche, V. Lazar, P. Dessen, F. Harper, et al. (2007)
Cancer Res. 67, 6253-6262
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Apoptosis: A Review of Programmed Cell Death.
S. Elmore (2007)
Toxicol Pathol 35, 495-516
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The Human Immunodeficiency Virus Type 1 Tat Protein Enhances Cryptosporidium parvum-Induced Apoptosis in Cholangiocytes via a Fas Ligand-Dependent Mechanism.
S. P. O'Hara, A. J. Small, J. B. Nelson, A. D. Badley, X.-M. Chen, G. J. Gores, and N. F. LaRusso (2007)
Infect. Immun. 75, 684-696
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Cell-specific expression of X-linked inhibitor of apoptosis in the anterior pituitary of streptozotocin-induced diabetic rats.
A. I Arroba, A. M Lechuga-Sancho, L. M Frago, J. Argente, and J. A Chowen (2007)
J. Endocrinol. 192, 215-227
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Increased apoptosis of lactotrophs in streptozotocin-induced diabetic rats is followed by increased proliferation.
A. I Arroba, A. M Lechuga-Sancho, L. M Frago, J. Argente, and J. A Chowen (2006)
J. Endocrinol. 191, 55-63
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Transgenic Expression of the Viral FLIP MC159 Causes lpr/gld-Like Lymphoproliferation and Autoimmunity.
M. Woelfel, J. Bixby, M. A. Brehm, and F. K.-M. Chan (2006)
J. Immunol. 177, 3814-3820
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Suppression of Fas-FasL coexpression by erythropoietin mediates erythroblast expansion during the erythropoietic stress response in vivo.
Y. Liu, R. Pop, C. Sadegh, C. Brugnara, V. H. Haase, and M. Socolovsky (2006)
Blood 108, 123-133
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Pathobiology of Idiopathic Ascending Aortic Aneurysms.
E. M. Kirsch, N. C. Radu, E. Allaire, and D. Y. Loisance (2006)
Asian Cardiovascular and Thoracic Annals 14, 254-260
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ANG II induces apoptosis of human vascular smooth muscle via extrinsic pathway involving inhibition of Akt phosphorylation and increased FasL expression.
Y. Li, Y.-H. Song, J. Mohler, and P. Delafontaine (2006)
Am J Physiol Heart Circ Physiol 290, H2116-H2123
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Glucocorticoid Modulatory Element-binding Protein 1 Binds to Initiator Procaspases and Inhibits Ischemia-induced Apoptosis and Neuronal Injury.
K. Tsuruma, T. Nakagawa, N. Morimoto, M. Minami, H. Hara, T. Uehara, and Y. Nomura (2006)
J. Biol. Chem. 281, 11397-11404
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Endothelial intercellular adhesion molecule (ICAM)-2 regulates angiogenesis.
M.-T. Huang, J. C. Mason, G. M. Birdsey, V. Amsellem, N. Gerwin, D. O. Haskard, A. J. Ridley, and A. M. Randi (2005)
Blood 106, 1636-1643
   Abstract »    Full Text »    PDF »
Mechanisms for the Apoptosis of Small Cell Lung Cancer Cells Induced by Anti-GD2 Monoclonal Antibodies: ROLES OF ANOIKIS.
W. Aixinjueluo, K. Furukawa, Q. Zhang, K. Hamamura, N. Tokuda, S. Yoshida, R. Ueda, and K. Furukawa (2005)
J. Biol. Chem. 280, 29828-29836
   Abstract »    Full Text »    PDF »
Pathologically elevated cyclic hydrostatic pressure induces CD95-mediated apoptotic cell death in vascular endothelial cells.
C. Hasel, S. Durr, A. Bauer, R. Heydrich, S. Bruderlein, T. Tambi, U. Bhanot, and P. Moller (2005)
Am J Physiol Cell Physiol 289, C312-C322
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Role of membrane sphingomyelin and ceramide in platform formation for Fas-mediated apoptosis.
M. Miyaji, Z.-X. Jin, S. Yamaoka, R. Amakawa, S. Fukuhara, S. B. Sato, T. Kobayashi, N. Domae, T. Mimori, E. T. Bloom, et al. (2005)
J. Exp. Med. 202, 249-259
   Abstract »    Full Text »    PDF »
Molecular Mechanism of Hepatic Injury in Coinfection with Hepatitis C Virus and HIV.
A. Balasubramanian, M. Koziel, J. E. Groopman, and R. K. Ganju (2005)
Clinical Infectious Diseases 41, S32-S37
   Abstract »    Full Text »    PDF »
A Novel Ligand-independent Apoptotic Pathway Induced by Scavenger Receptor Class B, Type I and Suppressed by Endothelial Nitric-oxide Synthase and High Density Lipoprotein.
X.-A. Li, L. Guo, J. L. Dressman, R. Asmis, and E. J. Smart (2005)
J. Biol. Chem. 280, 19087-19096
   Abstract »    Full Text »    PDF »
V{gamma}9V{delta}2 T cells use a combination of mechanisms to limit the spread of the pathogenic bacteria Brucella.
J. Oliaro, S. Dudal, J. Liautard, J.-B. Andrault, J.-P. Liautard, and V. Lafont (2005)
J. Leukoc. Biol. 77, 652-660
   Abstract »    Full Text »    PDF »
Functional Role of Death-associated Protein 3 (DAP3) in Anoikis.
T. Miyazaki, M. Shen, D. Fujikura, N. Tosa, H.-R. Kim, S. Kon, T. Uede, and J. C. Reed (2004)
J. Biol. Chem. 279, 44667-44672
   Abstract »    Full Text »    PDF »
Role of Fas-Mediated Apoptosis and Follicle-Stimulating Hormone on the Developmental Capacity of Bovine Cumulus Oocyte Complexes In Vitro.
F. J. Rubio Pomar, B. A.J. Roelen, K. A. Slot, H. T.A. van Tol, B. Colenbrander, and K. J. Teerds (2004)
Biol Reprod 71, 790-796
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Reactive Nitrogen Species-Induced Cell Death Requires Fas-Dependent Activation of c-Jun N-Terminal Kinase.
P. Shrivastava, C. Pantano, R. Watkin, B. McElhinney, A. Guala, M. L. Poynter, R. L. Persinger, R. Budd, and Y. Janssen-Heininger (2004)
Mol. Cell. Biol. 24, 6763-6772
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Role for Activating Transcription Factor 3 in Stress-Induced {beta}-Cell Apoptosis.
M. G. Hartman, D. Lu, M.-L. Kim, G. J. Kociba, T. Shukri, J. Buteau, X. Wang, W. L. Frankel, D. Guttridge, M. Prentki, et al. (2004)
Mol. Cell. Biol. 24, 5721-5732
   Abstract »    Full Text »    PDF »
The Human Papillomavirus 16 E6 Protein Binds to Fas-associated Death Domain and Protects Cells from Fas-triggered Apoptosis.
M. Filippova, L. Parkhurst, and P. J. Duerksen-Hughes (2004)
J. Biol. Chem. 279, 25729-25744
   Abstract »    Full Text »    PDF »
High Endothelial Venules of the Lymph Nodes Express Fas Ligand.
T. S. Kokkonen, M. T. Augustin, J. M. Makinen, J. Kokkonen, and T. J. Karttunen (2004)
Journal of Histochemistry & Cytochemistry 52, 693-699
   Abstract »    Full Text »    PDF »
Phosphatidylinositide 3-Kinase Priming Couples c-FLIP to T Cell Activation.
L.-W. Fang, T.-S. Tai, W.-N. Yu, F. Liao, and M.-Z. Lai (2004)
J. Biol. Chem. 279, 13-18
   Abstract »    Full Text »    PDF »
Requirement of p53 targets in chemosensitization of colonic carcinoma to death ligand therapy.
S. Wang and W. S. El-Deiry (2003)
PNAS 100, 15095-15100
   Abstract »    Full Text »    PDF »
Tempero-spatial dissociation between the expression of Fas and apoptosis after coronary occlusion.
Q Z Feng, T D Li, L X Wei, X Qiao, J Yi, L Wang, and T S Yang (2003)
Mol. Pathol. 56, 362-367
   Abstract »    Full Text »    PDF »
An Adenosine Analogue, IB-MECA, Down-Regulates Estrogen Receptor {alpha} and Suppresses Human Breast Cancer Cell Proliferation.
J. Lu, A. Pierron, and K. Ravid (2003)
Cancer Res. 63, 6413-6423
   Abstract »    Full Text »    PDF »
The Apoptosis-Necrosis Continuum: Insights from Genetically Altered Mice.
C. J. Zeiss (2003)
Veterinary Pathology 40, 481-495
   Abstract »    Full Text »    PDF »
Generation of a FasL-based Proapoptotic Fusion Protein Devoid of Systemic Toxicity due to Cell-surface Antigen-restricted Activation.
D. Samel, D. Muller, J. Gerspach, C. Assohou-Luty, G. Sass, G. Tiegs, K. Pfizenmaier, and H. Wajant (2003)
J. Biol. Chem. 278, 32077-32082
   Abstract »    Full Text »    PDF »
Interdimer processing mechanism of procaspase-8 activation.
D. W. Chang, Z. Xing, V. L. Capacio, M. E. Peter, and X. Yang (2003)
EMBO J. 22, 4132-4142
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Coenzyme Q10 Prevents Apoptosis by Inhibiting Mitochondrial Depolarization Independently of Its Free Radical Scavenging Property.
L. Papucci, N. Schiavone, E. Witort, M. Donnini, A. Lapucci, A. Tempestini, L. Formigli, S. Zecchi-Orlandini, G. Orlandini, G. Carella, et al. (2003)
J. Biol. Chem. 278, 28220-28228
   Abstract »    Full Text »    PDF »
Potentiation of a Tumor Cell Susceptibility to Autologous CTL Killing by Restoration of Wild-Type p53 Function.
J. Thiery, G. Dorothee, H. Haddada, H. Echchakir, C. Richon, R. Stancou, I. Vergnon, J. Benard, F. Mami-Chouaib, and S. Chouaib (2003)
J. Immunol. 170, 5919-5926
   Abstract »    Full Text »    PDF »
Carbon Monoxide Modulates Fas/Fas Ligand, Caspases, and Bcl-2 Family Proteins via the p38{alpha} Mitogen-activated Protein Kinase Pathway during Ischemia-Reperfusion Lung Injury.
X. Zhang, P. Shan, J. Alam, R. J. Davis, R. A. Flavell, and P. J. Lee (2003)
J. Biol. Chem. 278, 22061-22070
   Abstract »    Full Text »    PDF »
Glutamine delays spontaneous apoptosis in neutrophils.
T. C. Pithon-Curi, R. I. Schumacher, J. J. S. Freitas, C. Lagranha, P. Newsholme, A. C. Palanch, S. Q. Doi, and R. Curi (2003)
Am J Physiol Cell Physiol 284, C1355-C1361
   Abstract »    Full Text »    PDF »
Parkinsonian Mimetics Induce Aspects of Unfolded Protein Response in Death of Dopaminergic Neurons.
W. A. Holtz and K. L. O'Malley (2003)
J. Biol. Chem. 278, 19367-19377
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Early Events in the Anoikis Program Occur in the Absence of Caspase Activation.
P. Wang, A. J. Valentijn, A. P. Gilmore, and C. H. Streuli (2003)
J. Biol. Chem. 278, 19917-19925
   Abstract »    Full Text »    PDF »
Calcium/Calmodulin-dependent Protein Kinase II Regulation of c-FLIP Expression and Phosphorylation in Modulation of Fas-mediated Signaling in Malignant Glioma Cells.
B. F. Yang, C. Xiao, W. H. Roa, P. H. Krammer, and C. Hao (2003)
J. Biol. Chem. 278, 7043-7050
   Abstract »    Full Text »    PDF »
Bryostatin 1 and UCN-01 Potentiate 1-{beta}-D-Arabinofuranosylcytosine-Induced Apoptosis in Human Myeloid Leukemia Cells through Disparate Mechanisms.
S. Wang, Z. Wang, and S. Grant (2003)
Mol. Pharmacol. 63, 232-242
   Abstract »    Full Text »    PDF »

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