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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM061812-01
Application #
6189046
Study Section
Biochemistry Study Section (BIO)
Program Officer
Ikeda, Richard A
Project Start
2000-07-01
Project End
2005-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
1
Fiscal Year
2000
Total Cost
$229,871
Indirect Cost
Name
Yale University
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Tsuge, Tomohiko; Menon, Suchithra; Tong, Yingchun et al. (2011) CSN1 inhibits c-Jun phosphorylation and down-regulates ectopic expression of JNK1. Protein Cell 2:423-32
Wang, Xiping; Li, Wenjun; Piqueras, Raquel et al. (2009) Regulation of COP1 nuclear localization by the COP9 signalosome via direct interaction with CSN1. Plant J 58:655-67
Menon, Suchithra; Tsuge, Tomohiko; Dohmae, Naoshi et al. (2008) Association of SAP130/SF3b-3 with Cullin-RING ubiquitin ligase complexes and its regulation by the COP9 signalosome. BMC Biochem 9:1
Menon, Suchithra; Chi, Hongbo; Zhang, Huiyong et al. (2007) COP9 signalosome subunit 8 is essential for peripheral T cell homeostasis and antigen receptor-induced entry into the cell cycle from quiescence. Nat Immunol 8:1236-45
Pick, Elah; Lau, On-Sun; Tsuge, Tomohiko et al. (2007) Mammalian DET1 regulates Cul4A activity and forms stable complexes with E2 ubiquitin-conjugating enzymes. Mol Cell Biol 27:4708-19
Menon, Suchithra; Rubio, Vicente; Wang, Xiping et al. (2005) Purification of the COP9 signalosome from porcine spleen, human cell lines, and Arabidopsis thaliana plants. Methods Enzymol 398:468-81
Lykke-Andersen, Karin; Wei, Ning (2003) Gene structure and embryonic expression of mouse COP9 signalosome subunit 8 (Csn8). Gene 321:65-72
Lykke-Andersen, Karin; Schaefer, Laura; Menon, Suchithra et al. (2003) Disruption of the COP9 signalosome Csn2 subunit in mice causes deficient cell proliferation, accumulation of p53 and cyclin E, and early embryonic death. Mol Cell Biol 23:6790-7
Wang, Xiping; Feng, Suhua; Nakayama, Naomi et al. (2003) The COP9 signalosome interacts with SCF UFO and participates in Arabidopsis flower development. Plant Cell 15:1071-82
Zheng, Jianyu; Yang, Xiaoming; Harrell, Jennifer M et al. (2002) CAND1 binds to unneddylated CUL1 and regulates the formation of SCF ubiquitin E3 ligase complex. Mol Cell 10:1519-26

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