This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow An erratum has been published
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cao, X.
Right arrow Articles by Zhang, X.-k.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cao, X.
Right arrow Articles by Zhang, X.-k.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, November 2004, p. 9705-9725, Vol. 24, No. 22
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.22.9705-9725.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Retinoid X Receptor Regulates Nur77/Thyroid Hormone Receptor 3-Dependent Apoptosis by Modulating Its Nuclear Export and Mitochondrial Targeting

Xihua Cao, Wen Liu, Feng Lin, Hui Li, Siva Kumar Kolluri, Bingzhen Lin, Young-hoon Han, Marcia I. Dawson, and Xiao-kun Zhang*

Cancer Center, The Burnham Institute, La Jolla, California

Received 11 March 2004/ Returned for modification 27 May 2004/ Accepted 10 August 2004

Retinoid X receptor (RXR) plays a central role in the regulation of intracellular receptor signaling pathways by acting as a ubiquitous heterodimerization partner of many nuclear receptors, including the orphan receptor Nur77 (also known as thyroid hormone receptor 3 or NGFI-B), which translocates from the nucleus to mitochondria, where it interacts with Bcl-2 to induce apoptosis. Here, we report that RXR{alpha} is required for nuclear export and mitochondrial targeting of Nur77 through their unique heterodimerization that is mediated by dimerization interfaces located in their DNA-binding domain. The effects of RXR{alpha} are attributed to a putative nuclear export sequence (NES) present in its carboxyl-terminal region. RXR{alpha} ligands suppress NES activity by inducing RXR{alpha} homodimerization or altering RXR{alpha}/Nur77 heterodimerization. The RXR{alpha} NES is also silenced by RXR{alpha} heterodimerization with retinoic acid receptor or vitamin D receptor. Consistently, we were able to show that the mitochondrial targeting of the RXR{alpha}/Nur77 heterodimer and its induction of apoptosis are potently inhibited by RXR ligands. Together, our results reveal a novel nongenotropic function of RXR{alpha} and its involvement in the regulation of the Nur77-dependent apoptotic pathway.

* Corresponding author. Mailing address: The Burnham Institute, Cancer Center, 10901 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 646-3141. Fax: (858) 646-3195. E-mail: xzhang{at}burnham-inst.org.

Molecular and Cellular Biology, November 2004, p. 9705-9725, Vol. 24, No. 22
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.22.9705-9725.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Han, Y.-H., Zhou, H., Kim, J.-H., Yan, T.-d., Lee, K.-H., Wu, H., Lin, F., Lu, N., Liu, J., Zeng, J.-z., Zhang, X.-k. (2009). A Unique Cytoplasmic Localization of Retinoic Acid Receptor-{gamma} and Its Regulations. J. Biol. Chem. 284: 18503-18514 [Abstract] [Full Text]  
  • Wu, J. B., Chen, K., Ou, X.-M., Shih, J. C. (2009). Retinoic Acid Activates Monoamine Oxidase B Promoter in Human Neuronal Cells. J. Biol. Chem. 284: 16723-16735 [Abstract] [Full Text]  
  • Liu, J., Zhou, W., Li, S.-S., Sun, Z., Lin, B., Lang, Y.-Y., He, J.-Y., Cao, X., Yan, T., Wang, L., Lu, J., Han, Y.-H., Cao, Y., Zhang, X.-k., Zeng, J.-Z. (2008). Modulation of Orphan Nuclear Receptor Nur77-Mediated Apoptotic Pathway by Acetylshikonin and Analogues. Cancer Res. 68: 8871-8880 [Abstract] [Full Text]  
  • Chen, H.-Z., Zhao, B.-X., Zhao, W.-X., Li, L., Zhang, B., Wu, Q. (2008). Akt phosphorylates the TR3 orphan receptor and blocks its targeting to the mitochondria. Carcinogenesis 29: 2078-2088 [Abstract] [Full Text]  
  • Martin, L. J, Tremblay, J. J (2008). Glucocorticoids antagonize cAMP-induced Star transcription in Leydig cells through the orphan nuclear receptor NR4A1. J Mol Endocrinol 41: 165-175 [Abstract] [Full Text]  
  • Chakravarti, N., Lotan, R., Diwan, A. H., Warneke, C. L., Johnson, M. M., Prieto, V. G. (2007). Decreased Expression of Retinoid Receptors in Melanoma: Entailment in Tumorigenesis and Prognosis. Clin. Cancer Res. 13: 4817-4824 [Abstract] [Full Text]  
  • Lee, K.-W., Cobb, L. J., Paharkova-Vatchkova, V., Liu, B., Milbrandt, J., Cohen, P. (2007). Contribution of the orphan nuclear receptor Nur77 to the apoptotic action of IGFBP-3. Carcinogenesis 28: 1653-1658 [Abstract] [Full Text]  
  • Lim, S., Luo, M., Koh, M., Yang, M., bin Abdul Kadir, M. N., Tan, J. H., Ye, Z., Wang, W., Melamed, P. (2007). Distinct Mechanisms Involving Diverse Histone Deacetylases Repress Expression of the Two Gonadotropin {beta}-Subunit Genes in Immature Gonadotropes, and Their Actions Are Overcome by Gonadotropin-Releasing Hormone. Mol. Cell. Biol. 27: 4105-4120 [Abstract] [Full Text]  
  • Sun, K., Montana, V., Chellappa, K., Brelivet, Y., Moras, D., Maeda, Y., Parpura, V., Paschal, B. M., Sladek, F. M. (2007). Phosphorylation of a Conserved Serine in the Deoxyribonucleic Acid Binding Domain of Nuclear Receptors Alters Intracellular Localization. Mol. Endocrinol. 21: 1297-1311 [Abstract] [Full Text]  
  • Kim, H.-T., Kong, G., DeNardo, D., Li, Y., Uray, I., Pal, S., Mohsin, S., Hilsenbeck, S. G., Bissonnette, R., Lamph, W. W., Johnson, K., Brown, P. H. (2006). Identification of Biomarkers Modulated by the Rexinoid LGD1069 (Bexarotene) in Human Breast Cells Using Oligonucleotide Arrays. Cancer Res. 66: 12009-12018 [Abstract] [Full Text]  
  • Chow, E. K., Castrillo, A., Shahangian, A., Pei, L., O'Connell, R. M., Modlin, R. L., Tontonoz, P., Cheng, G. (2006). A role for IRF3-dependent RXR{alpha} repression in hepatotoxicity associated with viral infections. JEM 203: 2589-2602 [Abstract] [Full Text]  
  • Cunningham, N. R., Artim, S. C., Fornadel, C. M., Sellars, M. C., Edmonson, S. G., Scott, G., Albino, F., Mathur, A., Punt, J. A. (2006). Immature CD4+CD8+ Thymocytes and Mature T Cells Regulate Nur77 Distinctly in Response to TCR Stimulation. J. Immunol. 177: 6660-6666 [Abstract] [Full Text]  
  • Zeng, J.-Z., Sun, D.-F., Wang, L., Cao, X., Qi, J.-B., Yang, T., Hu, C.-Q., Liu, W., Zhang, X.-K. (2006). Hypericum sampsonii induces apoptosis and nuclear export of retinoid X receptor-alpha. Carcinogenesis 27: 1991-2000 [Abstract] [Full Text]  
  • Li, W., Yu, S.-W., Kong, A.-N. T. (2006). Nrf2 Possesses a Redox-sensitive Nuclear Exporting Signal in the Neh5 Transactivation Domain. J. Biol. Chem. 281: 27251-27263 [Abstract] [Full Text]  
  • Parrella, E., Gianni, M., Fratelli, M., Barzago, M. M., Raska, I. Jr, Diomede, L., Kurosaki, M., Pisano, C., Carminati, P., Merlini, L., Dallavalle, S., Tavecchio, M., Rochette-Egly, C., Terao, M., Garattini, E. (2006). Antitumor Activity of the Retinoid-Related Molecules (E)-3-(4'-Hydroxy-3'-adamantylbiphenyl-4-yl)acrylic Acid (ST1926) and 6-[3-(1-Adamantyl)-4-hydroxyphenyl]-2-naphthalene Carboxylic Acid (CD437) in F9 Teratocarcinoma: Role of Retinoic Acid Receptor {gamma} and Retinoid-Independent Pathways. Mol. Pharmacol. 70: 909-924 [Abstract] [Full Text]  
  • Stebbins, J. L., Jung, D., Leone, M., Zhang, X.-k., Pellecchia, M. (2006). A Structure-based Approach to Retinoid X Receptor-{alpha} Inhibition. J. Biol. Chem. 281: 16643-16648 [Abstract] [Full Text]  
  • Zimmerman, T. L., Thevananther, S., Ghose, R., Burns, A. R., Karpen, S. J. (2006). Nuclear Export of Retinoid X Receptor {alpha} in Response to Interleukin-1beta-mediated Cell Signaling: ROLES FOR JNK AND SER260. J. Biol. Chem. 281: 15434-15440 [Abstract] [Full Text]  
  • Lin, Y., Kokontis, J., Tang, F., Godfrey, B., Liao, S., Lin, A., Chen, Y., Xiang, J. (2006). Androgen and its receptor promote bax-mediated apoptosis.. Mol. Cell. Biol. 26: 1908-1916 [Abstract] [Full Text]  
  • Lee, K.-W., Ma, L., Yan, X., Liu, B., Zhang, X.-k., Cohen, P. (2005). Rapid Apoptosis Induction by IGFBP-3 Involves an Insulin-like Growth Factor-independent Nucleomitochondrial Translocation of RXR{alpha}/Nur77. J. Biol. Chem. 280: 16942-16948 [Abstract] [Full Text]  
  • Kolluri, S. K., Corr, M., James, S. Y., Bernasconi, M., Lu, D., Liu, W., Cottam, H. B., Leoni, L. M., Carson, D. A., Zhang, X.-k. (2005). The R-enantiomer of the nonsteroidal antiinflammatory drug etodolac binds retinoid X receptor and induces tumor-selective apoptosis. Proc. Natl. Acad. Sci. USA 102: 2525-2530 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»