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Science 288 (5468): 1053-1058

Copyright © 2000 by the American Association for the Advancement of Science

Noxa, a BH3-Only Member of the Bcl-2 Family and Candidate Mediator of p53-Induced Apoptosis

Eri Oda, 1* Rieko Ohki, 1* Hideki Murasawa, 1 Jiro Nemoto, 1 Tsukasa Shibue, 1 Toshiharu Yamashita, 2 Takashi Tokino, 2 Tadatsugu Taniguchi, 1 † Nobuyuki Tanaka 1

A critical function of tumor suppressor p53 is the induction of apoptosis in cells exposed to noxious stresses. We report a previously unidentified pro-apoptotic gene, Noxa. Expression of Noxa induction in primary mouse cells exposed to x-ray irradiation was dependent on p53. Noxa encodes a Bcl-2 homology 3 (BH3)-only member of the Bcl-2 family of proteins; this member contains the BH3 region but not other BH domains. When ectopically expressed, Noxa underwent BH3 motif-dependent localization to mitochondria and interacted with anti-apoptotic Bcl-2 family members, resulting in the activation of caspase-9. We also demonstrate that blocking the endogenous Noxa induction results in the suppression of apoptosis. Noxa may thus represent a mediator of p53-dependent apoptosis.

1 Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
2 Department of Molecular Biology, Cancer Research Institute, Sapporo Medical University School of Medicine, S1 W17, Chuo-Ku, Sapporo 060-8543, Japan.
*   These authors contributed equally to this report.

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Up-regulation of Mcl-1 Is Critical for Survival of Human Melanoma Cells upon Endoplasmic Reticulum Stress.
C. C. Jiang, K. Lucas, K. A. Avery-Kiejda, M. Wade, C. E. deBock, R. F. Thorne, J. Allen, P. Hersey, and X. D. Zhang (2008)
Cancer Res. 68, 6708-6717
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Severe acute respiratory syndrome coronavirus 3a protein activates the mitochondrial death pathway through p38 MAP kinase activation.
K. Padhan, R. Minakshi, M. A. B. Towheed, and S. Jameel (2008)
J. Gen. Virol. 89, 1960-1969
   Abstract »    Full Text »    PDF »
Oligomerization of BAK by p53 Utilizes Conserved Residues of the p53 DNA Binding Domain.
E. C. Pietsch, E. Perchiniak, A. A. Canutescu, G. Wang, R. L. Dunbrack, and M. E. Murphy (2008)
J. Biol. Chem. 283, 21294-21304
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Histone Arg Modifications and p53 Regulate the Expression of OKL38, a Mediator of Apoptosis.
H. Yao, P. Li, B. J. Venters, S. Zheng, P. R. Thompson, B. F. Pugh, and Y. Wang (2008)
J. Biol. Chem. 283, 20060-20068
   Abstract »    Full Text »    PDF »
p53-Dependent Apoptosis in the Inhibition of Spermatogonial Differentiation in Juvenile Spermatogonial Depletion (Utp14bjsd) Mice.
G. Shetty, S. H. Shao, and C. C. Y. Weng (2008)
Endocrinology 149, 2773-2781
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Bmi1 regulates memory CD4 T cell survival via repression of the Noxa gene.
M. Yamashita, M. Kuwahara, A. Suzuki, K. Hirahara, R. Shinnaksu, H. Hosokawa, A. Hasegawa, S. Motohashi, A. Iwama, and T. Nakayama (2008)
J. Exp. Med. 205, 1109-1120
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The Apoptotic Pathway Contributing to the Deletion of Naive CD8 T Cells during the Induction of Peripheral Tolerance to a Cross-Presented Self-Antigen.
W. L. Redmond, C.-H. Wei, H. T. C. Kreuwel, and L. A. Sherman (2008)
J. Immunol. 180, 5275-5282
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DUSP1 Is Controlled by p53 during the Cellular Response to Oxidative Stress.
Y.-X. Liu, J. Wang, J. Guo, J. Wu, H. B. Lieberman, and Y. Yin (2008)
Mol. Cancer Res. 6, 624-633
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WTp53 induction does not override MTp53 chemoresistance and radioresistance due to gain-of-function in lung cancer cells.
A. R. Cuddihy, F. Jalali, C. Coackley, and R. G. Bristow (2008)
Mol. Cancer Ther. 7, 980-992
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Bcl-2-family proteins and hematologic malignancies: history and future prospects.
J. C. Reed (2008)
Blood 111, 3322-3330
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Interferon-{gamma} Induces X-linked Inhibitor of Apoptosis-associated Factor-1 and Noxa Expression and Potentiates Human Vascular Smooth Muscle Cell Apoptosis by STAT3 Activation.
Y. Bai, U. Ahmad, Y. Wang, J. H. Li, J. C. Choy, R. W. Kim, N. Kirkiles-Smith, S. E. Maher, J. G. Karras, C. F. Bennett, et al. (2008)
J. Biol. Chem. 283, 6832-6842
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ATR-Chk2 Signaling in p53 Activation and DNA Damage Response during Cisplatin-induced Apoptosis.
N. Pabla, S. Huang, Q.-S. Mi, R. Daniel, and Z. Dong (2008)
J. Biol. Chem. 283, 6572-6583
   Abstract »    Full Text »    PDF »
A balance between NF-Y and p53 governs the pro- and anti-apoptotic transcriptional response.
P. Benatti, V. Basile, D. Merico, L. I. Fantoni, E. Tagliafico, and C. Imbriano (2008)
Nucleic Acids Res. 36, 1415-1428
   Abstract »    Full Text »    PDF »
BCL-2 dependence and ABT-737 sensitivity in acute lymphoblastic leukemia.
V. Del Gaizo Moore, K. D. Schlis, S. E. Sallan, S. A. Armstrong, and A. Letai (2008)
Blood 111, 2300-2309
   Abstract »    Full Text »    PDF »
BCL-2 Family Proteins: Critical Checkpoints of Apoptotic Cell Death.
N. N. Danial (2007)
Clin. Cancer Res. 13, 7254-7263
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