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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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Genomic Analyses of Musashi1 Downstream Targets Show a Strong Association with Cancer-related Processes.
R. de Sousa Abreu, P. C. Sanchez-Diaz, C. Vogel, S. C. Burns, D. Ko, T. L. Burton, D. T. Vo, S. Chennasamudaram, S.-Y. Le, B. A. Shapiro, et al. (2009)
J. Biol. Chem. 284, 12125-12135
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Bcl-2 family on guard at the ER.
E. Szegezdi, D. C. MacDonald, T. Ni Chonghaile, S. Gupta, and A. Samali (2009)
Am J Physiol Cell Physiol 296, C941-C953
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Induction of Proapoptotic Gene Expression and Recruitment of p53 Herald Ovarian Follicle Loss Caused by Polycyclic Aromatic Hydrocarbons.
J. K. Pru, T. Kaneko-Tarui, A. Jurisicova, A. Kashiwagi, K. Selesniemi, and J. L. Tilly (2009)
Reproductive Sciences 16, 347-356
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Simultaneous exposure to dietary acrylamide and corn oil developed carcinogenesis through cell proliferation and inhibition of apoptosis by regulating p53-mediated mitochondria-dependent signaling pathway.
X Zhang (2009)
Toxicology and Industrial Health 25, 101-109
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ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3-only protein NOXA in cancer cells.
Q. Wang, H. Mora-Jensen, M. A. Weniger, P. Perez-Galan, C. Wolford, T. Hai, D. Ron, W. Chen, W. Trenkle, A. Wiestner, et al. (2009)
PNAS 106, 2200-2205
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Control of mitochondrial apoptosis by the Bcl-2 family.
J. K. Brunelle and A. Letai (2009)
J. Cell Sci. 122, 437-441
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Overexpression of OATP1B3 Confers Apoptotic Resistance in Colon Cancer.
W. Lee, A. Belkhiri, A. C. Lockhart, N. Merchant, H. Glaeser, E. I. Harris, M. K. Washington, E. M. Brunt, A. Zaika, R. B. Kim, et al. (2008)
Cancer Res. 68, 10315-10323
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Hexane/Ethanol Extract of Glycyrrhiza uralensis Licorice Suppresses Doxorubicin-Induced Apoptosis in H9c2 Rat Cardiac Myoblasts.
H. J. Choi, M. R. Seon, S. S. Lim, J.-S. Kim, H. S. Chun, and J. H. Y. Park (2008)
Experimental Biology and Medicine 233, 1554-1560
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In vivo efficacy of the Bcl-2 antagonist ABT-737 against aggressive Myc-driven lymphomas.
K. D. Mason, C. J. Vandenberg, C. L. Scott, A. H. Wei, S. Cory, D. C. S. Huang, and A. W. Roberts (2008)
PNAS 105, 17961-17966
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The BH3-only protein Bik/Blk/Nbk inhibits nuclear translocation of activated ERK1/2 to mediate IFN{gamma}-induced cell death.
Y. A. Mebratu, B. F. Dickey, C. Evans, and Y. Tesfaigzi (2008)
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Apoptosis and Autophagy Induction in Mammalian Cells by Small Interfering RNA Knockdown of mRNA Capping Enzymes.
C. Chu and A. J. Shatkin (2008)
Mol. Cell. Biol. 28, 5829-5836
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Prognostic Impact of Bim, Puma, and Noxa Expression in Human Colon Carcinomas.
F. A. Sinicrope, R. L. Rego, K. Okumura, N. R. Foster, M. J. O'Connell, D. J. Sargent, and H. E. Windschitl (2008)
Clin. Cancer Res. 14, 5810-5818
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N-Myc downstream-regulated gene 2 is involved in p53-mediated apoptosis.
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Nucleic Acids Res. 36, 5335-5349
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Selection against PUMA Gene Expression in Myc-Driven B-Cell Lymphomagenesis.
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Mol. Cell. Biol. 28, 5391-5402
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Up-regulation of Mcl-1 Is Critical for Survival of Human Melanoma Cells upon Endoplasmic Reticulum Stress.
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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
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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
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