STRUCTURE AND FUNCTION OF THE COP9 SIGNALOSOME

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DESCRIPTION (adapted from applicant's abstract): The ability to regulate gene expression pattern in respond to extracellular signals is essential for the development and survival of all living organisms. The knowledge on the molecular mechanisms underlying such regulatory processes is necessary for understanding many complex biological phenomena including human diseases. The multi-component protein complex known as the COP9 signalosome was originally found to suppress the light activated gene expression and developmental responses in plants. It has been shown that the COP9 signalosome is structurally conserved between plants and animals, however the specific cellular functions and the role of this complex during animal development are unknown. The investigator's preliminary studies on individual subunits in mammalian cells have implied potential links of the COP9 signalosome to ubiquitin-proteasome mediated proteolysis and to cell signaling pathways. Using the subunit 1 (COPS1/GPS1/FUS6) as a model, Dr. Wei has further shown that this subunit confers a functional enhancing activity to repress light responses in Arabidopsis plant. In mammalian cells, the principal investigator's results showed that the S1/GPS1 subunit possess an intrinsic repressor domain that is separable from its structural domain required for complex assembly. Moreover, S1 can suppress signaling activation and mediate repression of gene expression by different mechanisms. To activate the overall goal of understanding the structure and function of COP9 signalosome, the principal investigator proposes: (1) to dissect the mechanisms of S1/GPS1 mediated repression in mammalian cells; (2) to investigate the physiological functions of the S1 repression domain in Arabidopsis by genetic approach; (3) to investigate the role of COP9 signalosome in the ubiquitin-proteasome pathway by examining the specific interaction with the machinery of the ubiquitin-proteasome pathway and the roles of the COP9 signalosome subunits in signal stimulated ubiquitination and degradation of representative molecules in mammalian cells; and (4) to establish an animal model of COP9 signalosome by gene targeting in mouse and to reveal its developmental role.