Summary of a probe development effort to identify inhibitors of COUP-TFII (NR2F2)
Steroid receptor chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) (1), an orphan nuclear receptor and member of the nuclear receptor superfamily, has been shown to be a critical transcriptional regulator in many different cancer types by promoting angiogenesis (2-4), cell proliferation and metastasis (5-11). COUP-TFII has widespread tissue distribution in human; detectable more ..
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center
Affiliation: The Scripps Research Institute, TSRI
Assay Provider: Ming-Jer Tsai, Baylor College of Medicine
Network: Molecular Library Probe Production Centers Network (MLPCN)
Grant Proposal Number: R01DK45641
Grant Proposal PI: Ming-Jer Tsai, Baylor College of Medicine
External Assay ID: COUPTFII_INH_SUMMARY
Name: Summary of a probe development effort to identify inhibitors of COUP-TFII (NR2F2)
Steroid receptor chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) (1), an orphan nuclear receptor and member of the nuclear receptor superfamily, has been shown to be a critical transcriptional regulator in many different cancer types by promoting angiogenesis (2-4), cell proliferation and metastasis (5-11). COUP-TFII has widespread tissue distribution in human; detectable expression has been found in every tissue type examined (12). Currently, the treatment for tumor angiogenesis focuses mainly on blocking VEGFR-2 signaling and has not been effective due to limited efficacy, eventually leading to resistance and/or relapse. COUP-TFII has been shown to promote tumor angiogenesis through modulating multiple angiogenic signals (VEGF/VEGFR-2, Angiopoietin 1/Tie2 and E2F-1) in many different types of cancer (13-14). In addition, COUP-TFII is overexpressed in prostate and several other cancers and is an excellent prognostic marker. By including COUP-TFII data with Cyclin D1, p21, PTEN, and Smad4 data in the prognosis, the prognostic accuracy is improved. The expression level of COUP-TFII and its role in regulating tumor growth and metastasis in prostate cancer has been examined, and these data indicate that COUP-TFII positively promotes prostate tumor growth and metastasis (15). These results provide the rational basis to posit that inhibition of COUP-TFII may offer a novel and broadly efficacious approach for anticancer intervention.
COUP-TFII has also been shown to regulate energy storage and expenditure. We have found that COUP-TFII heterozygous mice have increased mitochondrial biogenesis in white adipose tissue, which results in higher energy expenditure, resulting in resistance to high fat diet-induced obesity and improved glucose homeostasis due to increased insulin sensitivity at peripheral tissues (16). These results indicate that COUP-TFII has an important role in regulating adipocyte differentiation and energy metabolism. Therefore, COUP-TFII inhibitors could potentially serve as agents to improve insulin sensitivity, enhance energy metabolism, and decrease high fat diet-induced obesity.
Summary of Probe Development Effort:
This probe development effort is focused on the identification of inhibitors of COUP-TFII (NR2F2). All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.
1. Sagami, I., Tsai, S. Y., Wang, H., Tsai, M. J., and O'Malley, B. W. (1986) Identification of two factors required for transcription of the ovalbumin gene, Mol Cell Biol 6, 4259-4267.
2. Hanahan, D., and Weinberg, R. A. (2011) Hallmarks of cancer: the next generation, Cell 144, 646-674.
3. Lin, F. J., Chen, X., Qin, J., Hong, Y. K., Tsai, M. J., and Tsai, S. Y. (2010) Direct transcriptional regulation of neuropilin-2 by COUP-TFII modulates multiple steps in murine lymphatic vessel development, J Clin Invest 120, 1694-1707.
4. Pereira, F. A., Qiu, Y., Zhou, G., Tsai, M. J., and Tsai, S. Y. (1999) The orphan nuclear receptor COUP-TFII is required for angiogenesis and heart development, Genes Dev 13, 1037-1049.
5. Annecke, K., Schmitt, M., Euler, U., Zerm, M., Paepke, D., Paepke, S., von Minckwitz, G., Thomssen, C., and Harbeck, N. (2008) uPA and PAI-1 in breast cancer: review of their clinical utility and current validation in the prospective NNBC-3 trial, Adv Clin Chem 45, 31-45.
6. Harbeck, N., Kates, R. E., Schmitt, M., Gauger, K., Kiechle, M., Janicke, F., Thomassen, C., Look, M. P., and Foekens, J. A. (2004) Urokinase-type plasminogen activator and its inhibitor type 1 predict disease outcome and therapy response in primary breast cancer, Clin Breast Cancer 5, 348-352.
7. Litchfield, L. M., and Klinge, C. M. (2012) Multiple roles of COUP-TFII in cancer initiation and progression, J Mol Endocrinol 49, R135-148.
8. Litchfield, L. M., Riggs, K. A., Hockenberry, A. M., Oliver, L. D., Barnhart, K. G., Cai, J., Pierce, W. M., Jr., Ivanova, M. M., Bates, P. J., Appana, S. N., Datta, S., Kulesza, P., McBryan, J., Young, L. S., and Klinge, C. M. (2012) Identification and characterization of nucleolin as a COUP-TFII coactivator of retinoic acid receptor beta transcription in breast cancer cells, PLoS One 7, e38278.
9. Navab, R., Gonzalez-Santos, J. M., Johnston, M. R., Liu, J., Brodt, P., Tsao, M. S., and Hu, J. (2004) Expression of chicken ovalbumin upstream promoter-transcription factor II enhances invasiveness of human lung carcinoma cells, Cancer Res 64, 5097-5105.
10. Riggs, K. A., Wickramasinghe, N. S., Cochrum, R. K., Watts, M. B., and Klinge, C. M. (2006) Decreased chicken ovalbumin upstream promoter transcription factor II expression in tamoxifen-resistant breast cancer cells, Cancer Res 66, 10188-10198.
11. Shimizu, M., Cohen, B., Goldvasser, P., Berman, H., Virtanen, C., and Reedijk, M. (2011) Plasminogen activator uPA is a direct transcriptional target of the JAG1-Notch receptor signaling pathway in breast cancer, Cancer Res 71, 277-286.
12. Suzuki, T., Moriya, T., Darnel, A. D., Takeyama, J., and Sasano, H. (2000) Immunohistochemical distribution of chicken ovalbumin upstream promoter transcription factor II in human tissues, Mol Cell Endocrinol 164, 69-75.
13. Qin, J., Chen, X., Xie, X., Tsai, M. J., and Tsai, S. Y. (2010) COUP-TFII regulates tumor growth and metastasis by modulating tumor angiogenesis, Proc Natl Acad Sci U S A 107, 3687-3692.
14. Qin, J., Chen, X., Yu-Lee, L. Y., Tsai, M. J., and Tsai, S. Y. (2010) Nuclear receptor COUP-TFII controls pancreatic islet tumor angiogenesis by regulating vascular endothelial growth factor/vascular endothelial growth factor receptor-2 signaling, Cancer Res 70, 8812-8821.
15. Qin, J., Wu, S. P., Creighton, C. J., Dai, F., Xie, X., Cheng, C. M., Frolov, A., Ayala, G., Lin, X., Feng, X. H., Ittmann, M. M., Tsai, S. J., Tsai, M. J., and Tsai, S. Y. (2012) COUP-TFII inhibits TGF-beta-induced growth barrier to promote prostate tumorigenesis, Nature.
16. Li, L., Xie, X., Qin, J., Jeha, G. S., Saha, P. K., Yan, J., Haueter, C. M., Chan, L., Tsai, S. Y., and Tsai, M. J. (2009) The nuclear orphan receptor COUP-TFII plays an essential role in adipogenesis, glucose homeostasis, and energy metabolism, Cell Metab 9, 77-87.
17. Pipaon, C., Tsai, S. Y., and Tsai, M. J. (1999) COUP-TF upregulates NGFI-A gene expression through an Sp1 binding site, Mol Cell Biol 19, 2734-2745.
Summary, Summary AID, HTS, nuclear hormone receptor, NHR, reporter assay, luciferase, LUMI, COUPTFII, chicken ovalbumin upstream promoter, COUP transcription factor 2, NR2F2, ARP1, COUPTFB, NF-E3, NR2F1, SVP40, TFCOUP2, 1536, Scripps Florida, The Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN