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Science 289 (5482): 1159-1164

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

Cytochrome c Release and Apoptosis Induced by Mitochondrial Targeting of Nuclear Orphan Receptor TR3

Hui Li,1 Siva Kumar Kolluri,1 Jian Gu,1 Marcia I. Dawson,2 Xihua Cao,1 Peter D. Hobbs,3 Bingzhen Lin,1 Guo-quen Chen,1 Jiang-song Lu,4 Feng Lin,1 Zhihua Xie,1 Joseph A. Fontana,4 John C. Reed,1 Xiao-kun Zhang1*

TR3, an immediate-early response gene and an orphan member of the steroid-thyroid hormone-retinoid receptor superfamily of transcription factors, regulates apoptosis through an unknown mechanism. In response to apoptotic stimuli, TR3 translocates from the nucleus to mitochondria to induce cytochrome c release and apoptosis. Mitochondrial targeting of TR3, but not its DNA binding and transactivation, is essential for its proapoptotic effect. Our results reveal a mechanism by which a nuclear transcription factor translocates to mitochondria to initiate apoptosis.

1 The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
2 Molecular Medicine Research Institute, 325 East Middlefield Road, Mountain View, CA 94043, USA.
3 Retinoid Program, SRI, Menlo Park, CA 94025, USA.
4 Karmanos Cancer Institute, Wayne State University, and the John D. Dingel VA Medical Center, 4646 John R Street, Detroit, MI 48201, USA.
*   To whom correspondence should be addressed: E-mail: xzhang{at}burnham-inst.org


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   Abstract »    Full Text »    PDF »
Inhibitory Effect of 12-O-Tetradecanoylphorbol-13-acetate Alone or in Combination with All-trans-Retinoic Acid on the Growth of LNCaP Prostate Tumors in Immunodeficient Mice.
X. Zheng, R. L. Chang, X.-X. Cui, G. E. Avila, S. Lee, Y. P. Lu, Y. R. Lou, W. J. Shih, Y. Lin, K. Reuhl, et al. (2004)
Cancer Res. 64, 1811-1820
   Abstract »    Full Text »    PDF »
Gene Expression in HL60 Granulocytoids and Human Polymorphonuclear Leukocytes Exposed to Candida albicans{dagger}.
A. Mullick, M. Elias, P. Harakidas, A. Marcil, M. Whiteway, B. Ge, T. J. Hudson, A. W. Caron, L. Bourget, S. Picard, et al. (2004)
Infect. Immun. 72, 414-429
   Abstract »    Full Text »    PDF »
Transcriptional activation of known and novel apoptotic pathways by Nur77 orphan steroid receptor.
A. Rajpal, Y. A. Cho, B. Yelent, P. H. Koza-Taylor, D. Li, E. Chen, M. Whang, C. Kang, T. G. Turi, and A. Winoto (2003)
EMBO J. 22, 6526-6536
   Abstract »    Full Text »    PDF »
Mitogenic Effect of Orphan Receptor TR3 and Its Regulation by MEKK1 in Lung Cancer Cells.
S. K. Kolluri, N. Bruey-Sedano, X. Cao, B. Lin, F. Lin, Y.-H. Han, M. I. Dawson, and X.-k. Zhang (2003)
Mol. Cell. Biol. 23, 8651-8667
   Abstract »    Full Text »    PDF »
TR3 Orphan Nuclear Receptor Mediates Apoptosis through Up-regulating E2F1 in Human Prostate Cancer LNCaP Cells.
X. Mu and C. Chang (2003)
J. Biol. Chem. 278, 42840-42845
   Abstract »    Full Text »    PDF »
Gene expression analysis of thymocyte selection in vivo.
I. Schmitz, L. K. Clayton, and E. L. Reinherz (2003)
Int. Immunol. 15, 1237-1248
   Abstract »    Full Text »    PDF »
Phospholipid Scramblase 3 Controls Mitochondrial Structure, Function, and Apoptotic Response.
J. Liu, Q. Dai, J. Chen, D. Durrant, A. Freeman, T. Liu, D. Grossman, and R. M. Lee (2003)
Mol. Cancer Res. 1, 892-902
   Abstract »    Full Text »    PDF »
TR3/Nur77 in Colon Cancer Cell Apoptosis.
A. J. Wilson, D. Arango, J. M. Mariadason, B. G. Heerdt, and L. H. Augenlicht (2003)
Cancer Res. 63, 5401-5407
   Abstract »    Full Text »    PDF »
TR3 Orphan Receptor Is Expressed in Vascular Endothelial Cells and Mediates Cell Cycle Arrest.
E. K. Arkenbout, M. van Bragt, E. Eldering, C. van Bree, J. M. Grimbergen, P. H.A. Quax, H. Pannekoek, and C. J.M. de Vries (2003)
Arterioscler Thromb Vasc Biol 23, 1535-1540
   Abstract »    Full Text »    PDF »
Characterization of Transcriptional Regulation During Negative Selection In Vivo.
D. DeRyckere, D. L. Mann, and J. DeGregori (2003)
J. Immunol. 171, 802-811
   Abstract »    Full Text »    PDF »
Nur77 as a survival factor in tumor necrosis factor signaling.
S. Suzuki, N. Suzuki, C. Mirtsos, T. Horacek, E. Lye, S.-K. Noh, A. Ho, D. Bouchard, T. W. Mak, and W.-C. Yeh (2003)
PNAS 100, 8276-8280
   Abstract »    Full Text »    PDF »
The AF-1 Domain of the Orphan Nuclear Receptor NOR-1 Mediates Trans-activation, Coactivator Recruitment, and Activation by the Purine Anti-metabolite 6-Mercaptopurine.
K. D. S. A. Wansa, J. M. Harris, G. Yan, P. Ordentlich, and G. E. O. Muscat (2003)
J. Biol. Chem. 278, 24776-24790
   Abstract »    Full Text »    PDF »
Identification of the Antineoplastic Agent 6-Mercaptopurine as an Activator of the Orphan Nuclear Hormone Receptor Nurr1.
P. Ordentlich, Y. Yan, S. Zhou, and R. A. Heyman (2003)
J. Biol. Chem. 278, 24791-24799
   Abstract »    Full Text »    PDF »
Orphan Nuclear Receptor Nur77 Is Involved in Caspase-independent Macrophage Cell Death.
S. O. Kim, K. Ono, P. S. Tobias, and J. Han (2003)
J. Exp. Med. 197, 1441-1452
   Abstract »    Full Text »    PDF »

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