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Science 304 (5676): 1500-1502

Copyright © 2004 by the American Association for the Advancement of Science

Regulation of an ATG7-beclin 1 Program of Autophagic Cell Death by Caspase-8

Li Yu,1 Ajjai Alva,2 Helen Su,1 Parmesh Dutt,1 Eric Freundt,1,3 Sarah Welsh,1 Eric H. Baehrecke,2 Michael J. Lenardo1*

Abstract: Caspases play a central role in apoptosis, a well-studied pathway of programmed cell death. Other programs of death potentially involving necrosis and autophagy may exist, but their relation to apoptosis and mechanisms of regulation remains unclear. We define a new molecular pathway in which activation of the receptor-interacting protein (a serine-threonine kinase) and Jun amino-terminal kinase induced cell death with the morphology of autophagy. Autophagic death required the genes ATG7 and beclin 1 and was induced by caspase-8 inhibition. Clinical therapies involving caspase inhibitors may arrest apoptosis but also have the unanticipated effect of promoting autophagic cell death.

1 Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
2 Center for Biosystems Research, University of Maryland Biotechnology Institute, College Park, MD 20742, USA.
3 Weatherall Institute of Molecular Medicine, Oxford University, Headington, Oxford OX39D, UK.

* To whom correspondence should be addressed. E-mail: lenardo{at}

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Pivotal Role of the Cyclin-dependent Kinase Inhibitor p21WAF1/CIP1 in Apoptosis and Autophagy.
K. Fujiwara, S. Daido, A. Yamamoto, R. Kobayashi, T. Yokoyama, H. Aoki, E. Iwado, N. Shinojima, Y. Kondo, and S. Kondo (2008)
J. Biol. Chem. 283, 388-397
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Apoptosis and autophagy as mechanisms of dinoflagellate symbiont release during cnidarian bleaching: every which way you lose.
S. R Dunn, C. E Schnitzler, and V. M Weis (2007)
Proc R Soc B 274, 3079-3085
   Abstract »    Full Text »    PDF »
The Roles of Therapy-Induced Autophagy and Necrosis in Cancer Treatment.
R. K. Amaravadi and C. B. Thompson (2007)
Clin. Cancer Res. 13, 7271-7279
   Abstract »    Full Text »    PDF »
Dual roles of autophagy in the survival of Caenorhabditis elegans during starvation.
C. Kang, Y.-j. You, and L. Avery (2007)
Genes & Dev. 21, 2161-2171
   Abstract »    Full Text »    PDF »
Gtdap-1 promotes autophagy and is required for planarian remodeling during regeneration and starvation.
C. Gonzalez-Estevez, D. A. Felix, A. A. Aboobaker, and E. Salo (2007)
PNAS 104, 13373-13378
   Abstract »    Full Text »    PDF »
A Human scFv Antibody against TRAIL Receptor 2 Induces Autophagic Cell Death in Both TRAIL-Sensitive and TRAIL-Resistant Cancer Cells.
K.-J. Park, S.-H. Lee, T.-I. Kim, H.-W. Lee, C.-H. Lee, E.-H. Kim, J.-Y. Jang, K. S. Choi, M.-H. Kwon, and Y.-S. Kim (2007)
Cancer Res. 67, 7327-7334
   Abstract »    Full Text »    PDF »
Down-regulation of PU.1 by Methylation of Distal Regulatory Elements and the Promoter Is Required for Myeloma Cell Growth.
H. Tatetsu, S. Ueno, H. Hata, Y. Yamada, M. Takeya, H. Mitsuya, D. G. Tenen, and Y. Okuno (2007)
Cancer Res. 67, 5328-5336
   Abstract »    Full Text »    PDF »
Caspase Inhibition Sensitizes Inhibitor of NF-{kappa}B Kinase beta-deficient Fibroblasts to Caspase-independent Cell Death via the Generation of Reactive Oxygen Species.
M. J. May and L. A. Madge (2007)
J. Biol. Chem. 282, 16105-16116
   Abstract »    Full Text »    PDF »
Autophagy suppresses tumor progression by limiting chromosomal instability.
R. Mathew, S. Kongara, B. Beaudoin, C. M. Karp, K. Bray, K. Degenhardt, G. Chen, S. Jin, and E. White (2007)
Genes & Dev. 21, 1367-1381
   Abstract »    Full Text »    PDF »
Functional and physical interaction between Bcl-XL and a BH3-like domain in Beclin-1.
M. C. Maiuri, G. Le Toumelin, A. Criollo, J.-C. Rain, F. Gautier, P. Juin, E. Tasdemir, G. Pierron, K. Troulinaki, N. Tavernarakis, et al. (2007)
EMBO J. 26, 2527-2539
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