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Yih-Cherng LIOU
(Assistant
Professor)
Contact Information:
Departments of Biochemistry/Biological Sciences
14 Science Drive 4
Singapore 117543
Tel: (65) 6516 7711
Fax: (65) 6779 2486
E-mail :dbslyc@nus.edu.sg
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D. Phil. (Queen's, Canada), B. Sc. (NTOU,
Taiwan)
MAJOR RESEARCH INTERESTS
The phosphorylation of specific proteins on Ser/Thr residues preceding proline is thought to be a major cellular signaling mechanism; however, very little is known about how the phosphorylation actually regulates protein function. Recently, characterization of the novel peptidyl-prolyl cis/trans isomerase, Pin1 has demonstrated a new aspect of this post-phosphorylation regulation mechanism.
Interestingly, Pin1 is highly overexpressed in human breast cancer. Impor tantly, overexpression of Pin1 can lead to up-regulation of cyclin D1 and transformation of breast epithelial cells in collaboration with the oncogenic pathways.
In contrast, in Alzheimer's diseased brains, Pin1 binds phosphorylated tau and is sequestered into the neurofibrillary tangles, resulting in depletion of soluble Pin1. Previously, we have discovered that Pin1 knockout mice display several phenotypes, including impaired mammary gland and progressive age-dependent neuronal degenerative abnormalities, suggesting that Pin1 plays a pivotal role in the development of cancer, and in the pathogenesis of AD and neurodegeneration. However, it is not much known about how Pin1 modulates its phosphorylated subtracts and how this post-phosphorylation mechanism affects normal cellular and neuron functions.
Our future research directions lie in the area of how protein structure impacts signaling in the cells. The objectives are to characterize further the biology function of Pin1. We are interested in unders tanding how this prolyl isomerase regulates its targets by changing the conformation on the pSer/Thr-Pro motifs, in particular in neurodegenerative mechanism. We will also focus on elucidating the role and mechanism of prolyl isomerases in regulating cellular signaling mechanisms, using in vivo and in vitro techniques, as well as animal models.
Briefly, our research areas will include:
- Protein structural dynamics and biological function relationship
- Molecular signaling of neuronal degeneration and cancer
- Animal models for human neurodegeneration diseases
Publications
Tang BL & Liou YC (2006) Novel modulators of amyloid-beta precursor protein (APP) processing . J. Neurochem. In press.
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Buschdorf JP, Li Chew L, Zhang B, Cao Q, Liang FY, Liou YC, Zhou YT, Low BC. (2006) Brain-specific BNIP-2-homology protein Caytaxin relocalises glutaminase to neurite terminals and reduces glutamate levels. J Cell Sci. 119:3337-50.
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Ryo A, Togo T, Nakai T, Hirai A, Nishi M, Yamaguchi A, Suzuki K, Hirayasu Y, Kobayashi H, Perrem K, Liou YC, Aoki I. (2006) Prolyl-isomerase Pin1 accumulates in lewy bodies of parkinson disease and facilitates formation of alpha-synuclein inclusions. J Biol Chem. 281(7):4117-25.
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Whiteman M, Chua YL, Zhang D, Duan W, Liou YC, Armstrong JS. (2006) Nitric oxide protects against mitochondrial permeabilization induced by glutathione depletion: role of S-nitrosylation? BBRC6;339(1):255-62.
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Wulf G, Garg P, Liou YC, Iglehart D, Lu KP. (2004) Modeling breast cancer in vivo and ex vivo reveals an essential role of Pin1 in tumorigenesis. EMBO J., 23, 3397-407.
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Ryo A, Suizu F., Yoshida Y., Perrem K., Liou YC, Wulf G., Rottapel R, Yamaoka S, and Lu K.P. (2003) Regulation of NF-kappaB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA. Mol Cell. 12:1413-26.
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Liou, YC, Sun, A., Ryo, A., Zhou, X.Z., Yu, Z.X., Huang, H., Uchida, T., Bronson, R., Bing, G., Li, X., Hunter, T., and Lu., K.P. (2003) Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration. Nature, 424, 556-61.
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Wulf G, Ryo A, Liou YC, and Lu K.P. (2003) The prolyl isomerase Pin1 in breast development and cancer. Breast Cancer Res. 2003;5(2):76-82.Review.
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Ryo A, Liou YC, Lu KP, and Wulf G. (2003) Prolyl isomerase Pin1: a catalyst for oncogenesis and a potential therapeutic target in cancer. J Cell Sci. 116:773-83.
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Wulf G.M., Liou YC, Ryo A., Lee S.W., and Lu K.P. (2002) Role of Pin1 in the regulation of p53 stability and p21 transactivation, and cell cycle checkpoints in response to DNA damage. J. Biol. Chem. 277:47976-9.
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Lu K.P., Liou, YC, and Vincent, I. (2003) Proline-directed phosphorylation and isomerization in mitotic regulation and in Alzheimer's disease. Bioessays 25,174-181.
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Lu, K. P., Liou, Y.C., and Zhou, X. Z. (2002) Pinning down proline-directed phosphorylation signaling. Trends Cell Biol. 12, 164-172.
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Ryo, A., Liou, Y.C., Wulf, G., Nakamura, N., Lee, S. W. and Lu. K.P. (2002) Pin1 is a downstream target of E2F and is essential for the Neu/Ras-induced transformation of mammary epithelial cells. Mol. Cell Biol. 22, 5281-5295
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Liou Y.C., Ryo, A., Huang, H.K., Lu, P.J., Bronson, R., Fujimori, F., Uchida, T., Hunter, T., and Lu, K.P. (2002) Loss of Pin1 function in the mouse causes phenotypes resembling cyclin D1-null phenotypes. Proc. Natl. Acad. Sci. U.S.A. 99, 1335-40. (Track II)
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Lu, P.J., Xiao, Z., Liou, Y.C., and Lu. K.P. (2002) Critical role of WW domain phosphorylation in regulating phosphoserine binding activity and Pin1 function. J Biol Chem. 277, 2381-4.
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Ryo, A., Liou, Y.C.*, Nakamura, N.*, Wulf, G.*, and Lu. K.P. (2001) Prolyl isomerase Pin1 regulates subcellular localization and turnover of beta-catenin by inhibiting its interaction with APC. Nature Cell Biol. 3:793-801 (*, These authors contributed equally).
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