TR3, also called NGFI-B or nur77, is an immediate-early response gene and an orphan member of the steroid/thyroid/retinoid receptor superfamily. TR3/nur77 exerts not only mitogenic but also apoptotic effects in cancer cells in response to different stimuli. How TR3/nur77 mediates the opposing activities, survival and death, is interesting and remains unknown. Recently, we observed that TR3/nur77 acts in the nucleus to induce cell proliferation by inhibiting expression of retinoic acid receptor beta (RARbeta), a potent growth inhibitor. In addition, we found that TR3/nur77, in response to apoptosis-inducing agents, translocates from the nucleus to the cytoplasm, where it resides in mitochondria to induce cytochrome c release and apoptosis. These results led us to propose that TR3/nur77 acts in the nucleus to induce cell proliferation by inhibiting RARbeta expression. whereas it acts in mitochondria to trigger cytochrome c release and apoptosis. In the proposed studies, we plan to: 1. Investigate whether cellular localization of TR3/nur77 defines its biological functions in various cell types. 2. Study the inhibitory effect of TR3/nur77 on RARbeta expression. 3. Determine whether and how mitochondrial localization of TR3/nur77 triggers cytochrome c release and apoptosis. 4. Explore the possibility that Bcl-2 acts to mediate TR3/nur77 mitochondrial targeting and its induction of cytochrome c release through its physical interaction with TR3/nur77. 5. Determine the effects of TR3/nur77 phosphorylation by Jun N-terminal kinase (JNK) on its nuclear export and mitochondrial targeting. 6. Evaluate mitogenic and apoptotic effects of TR3/nur77 on tumor growth in nude mice. Results from these studies will enhance our understanding of the mechanisms by which TR3/nur77 exerts mitogenic and apoptotic activities and its role in regulating tumor development, and may provide valuable information to determine the feasibility of using TR3/nur77 as a molecular target for developing new generation of anti-cancer drugs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA087000-05
Application #
6914950
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2001-07-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2007-06-30
Support Year
5
Fiscal Year
2005
Total Cost
$307,125
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Han, Young-Hoon; Zhou, Hu; Kim, Jin-Hee et al. (2009) A unique cytoplasmic localization of retinoic acid receptor-gamma and its regulations. J Biol Chem 284:18503-14
Kolluri, Siva Kumar; Zhu, Xiuwen; Zhou, Xin et al. (2008) A short Nur77-derived peptide converts Bcl-2 from a protector to a killer. Cancer Cell 14:285-98
Liu, Jie; Zhou, Wen; Li, Shao-Shun et al. (2008) Modulation of orphan nuclear receptor Nur77-mediated apoptotic pathway by acetylshikonin and analogues. Cancer Res 68:8871-80
Zhang, Xiao-kun (2007) Targeting Nur77 translocation. Expert Opin Ther Targets 11:69-79
Zeng, Jin-Zhang; Sun, De-Fu; Wang, Li et al. (2006) Hypericum sampsonii induces apoptosis and nuclear export of retinoid X receptor-alpha. Carcinogenesis 27:1991-2000
Han, Y-H; Cao, X; Lin, B et al. (2006) Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt. Oncogene 25:2974-86
Lin, Bingzhen; Kolluri, Siva Kumar; Lin, Feng et al. (2004) Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell 116:527-40
Kolluri, Siva Kumar; Bruey-Sedano, Nathalie; Cao, Xihua et al. (2003) Mitogenic effect of orphan receptor TR3 and its regulation by MEKK1 in lung cancer cells. Mol Cell Biol 23:8651-67
James, Sharon Y; Lin, Feng; Kolluri, Siva Kumar et al. (2003) Regulation of retinoic acid receptor beta expression by peroxisome proliferator-activated receptor gamma ligands in cancer cells. Cancer Res 63:3531-8