Ming-Jer Tsai, Ph.D.
C.C. Bell Distinguished Service Professor
Departments of Molecular and Cellular Biology and Medicine and Program of Development
Ph.D.: University of California, Davis
Postdoctoral training: University of Texas, M.D. Anderson Cancer Center, Houston
Roles of NucleaRoles of Nuclear Receptors COUP-TFs and Coregulator, SRC-3/AIB1, in Development and Diseases
COUP-TFs are orphan members of the steroid/thyroid receptor superfamily. We cloned these genes in 90’s. In order to understand the physiological function of COUP-TFs, we have collaborated with Dr. Sophia Tsai to generate various mutations in mouse. The results indicate that COUP-TFs play important roles in development, range from neuronal development to organogenesis. We have identified that COUP-TFII mediates hedgehog signaling in regulating stomach and uterus development and retinoic acid signal in diaphragm development. The downstream effectors are also identified. By regulating Notch signaling, COUP-TFII exerts its control in determining the arterial-venous identity and Leydig cell development; BMP2 in induction of decidual response in the uterus; Pax2/6 in retina and optic stalk formation in the eye; WT1and Wnt4 in kidney development; PGC1a in adipocyte differentiation as well as energy metabolism and fuel usage in the muscle and heart; Wnt signaling, PPARg, Runx2 and Sox9 in mesenchymal cell fate determination; and steroidogenesis enzymes in progesterone and testosterone synthesis. COUP-TFI null mutants die right after birth. Upon examination of the PNS and CNS, we found that neural development, brain regionalization, axon myelination and guidance are defective. These data clearly demonstrate that both COUP-TFs possess vital physiological functions. In addition, COUP-TFs are also important for various diseases, such as congenital diaphragmatic hernia (CDH), congenital heart defects (CHD), heart failure, coloboma, kidney diseases, insulin resistant and cancers. In the cancer area, we have shown that COUP-TFII is essential for proper angiogenesis by regulating the expression of angiogenic factors, angiopoietin-1, VEGFR1, Notch signaling molecules and E2F-1 in tumor microenvironment. This notion was further supported by the fact that breast and pancreatic tumor growth is severely hampered in COUP-TFII null background. In addition, COUP-TFII expression is upregulated in prostate cancer patient and it is important for cell autonomous function of tumor cells. COUP-TFII mediates PTEN/AKT signaling in tumor growth and metastasis by regulating genes important for cell growth and by interfering TGFb cancer barrier. Currently we are continuing analyzing their roles in organogenesis and dissect their underlying mechanisms as well as searching for ligands to devise treatment of the above mentioned diseases.
The steroid/thyroid hormone receptor superfamily consists of a large number of members and they are transcription factors. In order for these transcription factors to function, transcriptional coactivators and corepressors are needed. In collaboration with Dr. O’Malley’s laboratory, we have isolated the first nuclear receptor coactivator, SRC-1. Subsequently, two related coactivators, SRC-2 and -3 are identified. Major focus of our laboratory in this particular area is to dissect tumor promotional role of SRC-2 and SRC-3/AIB1. We have demonstrated that SRC-3/AIB1 is over-expressed in prostate cancer patients. Furthermore, we have demonstrated that SRC-3/AIB1 promote cell growth, proliferation and migration and invasion and studied the underlying mechanism. We found that SRC-3/AIB1 coordinately and directly regulates the expression of many components of the IGF/PI3K growth factor and NFkB signal pathways at the transcriptional level to induce tumor cell growth and metastasis. SRC-2 is one of the genes shown to related to the prostate cancer. We showed that it enhances the prostate tumor growth. In addition, similar to COUP-TFII, SRC-2 is also upregulated and important for the fuel usage during heart failure. Currently, we continue to study its mechanism of action and devise methods to interfere these pathways for cancer treatment.
Baylor College of Medicine
One Baylor Plaza
Houston, Texas 77030
- Lin F-J, Chen X., Qin J, Hong Y-K, Tsai, M-J, and Tsai, SY. (2010). Direct transcriptional regulation of Nrp2 by COUP-TFII modulates multiple steps in lymphatic vessel development. J. Clinical Investigation 120: 1694-1707.
- 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.
- Qin J, Chen X, Xie X, Tsai M-J, and Tsai SY. (2010). COUP-TFII controls tumor growth and metastasis through regulating multiple angiogenesis signaling pathways in the tumor microenvironment. Proc. Natl. Acad. Sci. USA 284: 36167-36174.
- 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.
- Yan J, Erdem H, Ayala G, Ittmann M, Yu-Lee LY, Tsai SY and Tsai M-J (2008). SRC-3/AIB1 promotes cell motility and invasiveness through focal adhesion turnover and matrix metalloproteinase expression. Cancer Research 68: 5460-5468.
- 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.
- Yan J, Yu C-T, Ozen M, Ittmann M, Tsai SY and Tsai M-J. (2006). Steroid receptor coactivator-3 and AP-1 coordinately regulates the transcription of components of the IGF/AKT signaling pathway. Cancer Research 66:11039-11046.
- You LR, Takamoto N, Tanaka T, Kodama T, DeMayo FJ, Tsai SY and Tsai M-J. (2005). Mouse lacking COUP-TFII as an animal model of Bochdalek-type congenital diaphragmatic hernia. Proc. Natl. Acad. Sci. USA 102:16351-16356.
- You L-R, Lin F-J, Lee CT, DeMayo FJ, Tsai M-J and Tsai SY. (2005). Suppression of Notch signaling by the nuclear receptor COUP-TFII is required for the establishment of vein identity. Nature 435:98-104.
- Bramblett DE, Pennesi ME, Wu SM and Tsai M-J. (2004). The transcription factor Bhlhb4 is required for rod bipolar cell maturation. Neuron 43:779-793.