Sophia Y. Tsai, Ph.D.
Department of Molecular and Cellular Biology
Ph.D.: University of California, Davis
Postdoctoral training: Cornell University, Ithaca
M.D. Anderson Cancer Center, Houston
COUP-TFII and Vein Identity, Angiogenesis, Diabetes and Obesity and Kidney Disease
My research interests focus on understanding the physiological role of an orphan nuclear receptor, COUP-TFII. Our studies could be divided into three areas:
1. Tumor growth and metastasis: Using mouse model, we showed previously that COUP-TFII suppresses notch-signaling pathway to confer vein identity. Since lymphatic vessels derive from veins, the formation of lymphatic vessels is impaired in the absence of COUP-TFII. Recently, we showed that COUP-TFII regulates angiogenesis and tumor progression within the tumor microenvironment. Conditional ablation of COUP-TFII in adult mice resulted in defective angiogenesis and compromised tumor growth in xenograft and in spontaneous mouse tumor models. COUP-TFII regulates multiple genes in various growth signaling pathways to promote tumor growth and tumor metastasis. Since COUP-TFII expression is elevated in prostate cancer patient samples, we are studying the cell autonomous function of COUP-TFII in tumor cells. Using cell culture and animal model, we demonstrated that COUP-TFII plays a cell autonomous function to promote tumor growth in prostate tumorigenesis.
2. Cardiovascular development: Congenital heart defects are common genetic defects of infants. A hypomorphic mutant of COUP-TFII exhibits defects in formation of atrial-ventricular septum and coronary vessels, defects commonly seen in CHD patients. Ablation of COUP-TFII in atrial cardiomyocytes, converts atrial cardiomyocytes to adopt ventricular fate, while ectopic-expression of COUP-TFII in ventricular cardiomyocytes changes ventricular identity to atrial identity.
3. Energy metabolism and diseases: It is also shown that the expression of COUP-TFII is elevated in heart patients with familial heart disease and in a pressure overloaded mouse model. Heart failure is a major medical problem in US. To address the potential role of COUP-TFII in energy metabolism in the heart, we generated a mouse model overexpressing COUP-TFII in the heart. We showed that elevated COUP-TFII expression results in the suppression of the expression of key enzymes essential for fatty acid trafficking and oxidation, suggesting a defect in usage of lipid as fuel. The expression of many enzymes involved in fatty acid metabolism is regulated by the PGC/ERR axis, suggesting COUP-TFII might control the PGC/ERR axis to regulate fuel usage and mitochondrial function, leading to dysregulation of energy metabolism.
The major questions remaining to be addressed are: How is COUP-TFII being regulated in different tissues? What are the direct downstream targets of COUP-TFII? What are the molecular pathways impacted by COUP-TFII to confer all these defects? Understanding the function of COUP-TFII may provide new novel targets for future treatment of cardiovascular and metabolic diseases and cancer.
1.The role of COUP-TFII in prostate cancer
2.The role of COUP-TFII in energy metabolism in heart and muscle
3. The role of COUP-TFII in cardiovascular development and diseases
Baylor College of Medicine
One Baylor Plaza, DeBakey M707
Houston, TX 77030
- Xie X, Qin J, Lin S-H, Tsai SY and Tsai M-J. (2011). COUP-TFII modulates mesenchymal cell lineage commitment and differentiation. Proc. Natl. Acad. Sci. USA, 108: 14843-14848. PMID: 21873211
- Qin J, Chen X, Yu-Lee L, Tsai M-J and Tsai SY. (2010). Nuclear receptor COUP-TFII controls pancreatic islet tumor angiogenesis by regulating VEGF/VEGFR-2 signaling. Cancer Res. 70: 8812-8821. PMID: 20978203; PMCID: PMC: 2970665
- Lin FJ, Chen X, Qin J, Hong YK, Tsai MJ, Tsai SY. (2010). Direct transcriptional regulation of neuropilin-2 by COUP-TFII modulates multiple steps in murine lymphatic vessel development. J. Clin Investigation. 120:1694-1707 PMCID: PMC2860940
- Qin J, Chen X, Xie X, Tsai MJ, Tsai SY. (2010). COUP-TFII regulates tumor growth and metastasis by modulating tumor angiogenesis. Proc Natl Acad Sci 107:2431-6 PMCID: PMC2840495
- Tang K, Park J-I, Jamrich M, Tsai SY and Tsai M-J. (2010). COUP-TFs regulate eye development by controlling factors essential for optic vesicle morphogenesis. Development 137: 725-734 PMCID: PMC2827684
- Li L, Xie X, Qin J, Jeha G, Saha PK, Yan J, Haueter CM, Chan L, Tsai SY and Tsai M-J.(2009). The Nuclear orphan receptor COUP-TFII plays an essential role in adipogenesis, glucose homeostasis and energy metabolism. Cell Metabolism 9: 77-87 PMCID: PMC2630393.
- Kurihara K, Lee D-K, Petit FG, Jeong J, Lee K, Lydon JP, DeMayo FJ, Tsai M-J and Tsai SY. (2007). COUP-TFII mediates progesterone regulation of uterine implantation by controlling ER activity. PLoS Genetics 3: e102, 1053-1064 PMCID: PMC1892047.
- Petit FG, Jamin SP, Behringer RR, DeMayo FJ, Tsai M-J and Tsai SY. (2007). Deletion of the orphan nuclear receptor COUP-TFII in uterus leads to placental deficiency. Proc. Natl. Acad. Sci. USA 104: 6293-6298 PMCID: PMC1851059.
- You LR, TakamotoN, Yu CT,Tanaka T, Kodama T, DeMayo FJ, Tsai SY and Tsai MJ.(2005). Mouse lacking COUP-TFII as an animal model of Bochdalek-type congenital diaphragmatic hernia. Proc.Natl.Acad.Sci., 102(45):16351-16356 PMCID: PMC1283449.
- You L-R, Lin F-J, Lee CT, DeMayo FJ, Tsai M-Jand Tsai SY. (2005). COUP-TFII suppression of Notch signaling regulates vein identity. Nature, 435, 98-104 PMID: 15875024