The study of regulatory factors for the C-terminal coactivation domain of glucocorticoid-receptor- interacting-protein 1 (GRIP1) functions

• Main Authors: Shu-Ting Liu, 劉淑婷
• Other Authors: Shih-Ming Huang
• Format: Others
• Language: zh-TW
• Published: 2008
• Online Access: http://ndltd.ncl.edu.tw/handle/97625255370599833518

碩士 === 國防醫學院 === 生物化學研究所 === 96 === Glucocorticoid receptor-interacting protein 1 (GRIP1), one of the p160 family co-activator proteins, primarily mediates transcriptional activation by nuclear receptors via three activation domains that recruit at least three secondary co-activators, CBP/p300, co-activator-associated arginine methyltransferase 1, and coiled-coil co-activator (CoCoA) which exert histone acetyltransferase and/or arginine methyltransferase enzyme activity. The regulatory mechanisms underlying the GRIP1 co-activation functions involve its post-translational sumoylation and ubiquitin-conjugating enzyme 9 (UBC9), but are not well understood. This thesis demonstrates that promyelocytic leukaemia protein (PML) and UBC9 specifically act on the C-terminal transactivation activity of GRIP1 using the GRIP1 N-terminal co-activator, CoCoA, and some truncated GRIP1 fragments. The mechanisms of enhancement by PML and UBC9 both suppressed the repressive effect within the GRIP1 C-terminal region depended on the sumoylation status of PML, but not on the sumo-conjugating enzyme activity of UBC9. Daxx is not the primary target of PML for the regulation of GRIP1 co-activator functions, whereas, PML-RAR has the ability to suppress the enhancement of PML on GRIP1, mediating the truth of the hetero-dimerization of PML and PML-RAR. The activities of PML and UBC9 might be involved in the regulation of GRIP1 transactivation activity to enhance the nuclear receptor co-activator functions of GRIP1. This thesis provides new insights into the sumoylation status, the common C-terminal structure of PML family proteins, and the nuclear localization signal of PML in the regulation of the GRIP1 co-activator functions.