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泛素化系统在NF-kB信号转导中以及哺乳动物胚胎干细胞和配子发生中的作用 

Biochemical regulation of NF-kB, embryonic stem cells and gamete biogenesis by the ubiquitination system.
In cells, many proteins undergo post-translational modifications under certain physiological as well as pathological conditions. As many as 300 post-translational modifications of proteins are known to occur in cells: phosphorylation, acetylation, methylation, ubiquitination and so on.
Ubiquitin is a small protein of only 76 amino acids in length that is ubiquitously expressed in all cells and is highly conserved from yeast to human. Modification of proteins by ubiquitin is achieved through the process called ubiquitination in which the carboxyl group of the last glycine residue at the C-terminus of ubiquitin is covalently attached to the ε-amino group of a lysine residue on the target protein resulting in the formation of an isopeptide bond. The ubiquitination process is a coordinated three-step enzymatic reaction (Figure 1). In human genome it encodes more than 40 E2s and 500 E3s.
Ubiquitination is rich in information and regulates a variety of cellular processes including but not limited to protein degradation, endocytosis and intracellular protein trafficking, kinase activation and DNA repair. The importance of the ubiquitination system is comparable to that of kinases. Studies on the ubiquitination system and its regulation on other cellular processes are becoming the forefront of biomedical research.

Figure 1. The protein ubiquitination system. The ubiquitination cascade involves three enzymatic steps. Ubiquitin is first activated by the ubiquitin activation enzyme E1 with the hydrolysis of ATP. Ubiquitin is then transferred to a ubiquitin conjugating enzyme E2. Ubiquitin loaded on E2 is then transferred to a substrate with the help of ubiquitin ligase E3. Five subfamily of E3s have been described (HECT-, RING-, U box-, PHD-, and A20 ZnF-domain containing E3s). Protein substrate can be mono- or poly-ubiquitinated. Polyubiquitin chains can be K6, K11, k27, k29, k33, K48, or K63 linked. Linear polyubiquitin chains (shown as ‘NH’ linkage) and mixed-linkage chains (shown as ‘Kx’ linkage) have also been reported.  Polyubiquitin chains can be disassembled by the deubiquitination enzymes. Mono- or poly-ubiquitination is rich in information and involved in protein degradation, endocytosis and intracellular protein trafficking, kinase activation and DNA repair.
The transcription factor NF-κB is important in immune, inflammatory and stress responses and has been implicated in a number of diseases such as cancer (breast cancer, ovary cancer, lung cancer, liver cancer etc.), arthritis, and neurodegenerative diseases. It can be activated by a variety of biological, physical and chemical agents such as TNFa, IL1b, LPS, influenza viruses, and UV radiation. The activation of NF-κB is highly regulated. In the past twelve years, its regulation by the ubiquitination system has been under intensive study and has become a paradigm for crosstalk between the ubiquitination system and a traditional signaling pathway. In this paradigm, several components and steps in the NF-κB pathway are under tight regulation, either positively or negatively, by the ubiquitination system, which involves both traditional and non-traditional functions of the ubiquitination system (Figure 2).

Figure 2. The NF-kB signaling pathway.
One focus of our group is to study how the ubiquitination system regulates the activation of IKK-NF-κB signaling pathway. We are exploring a variety of modern biomedical research technology (Biochemistry, Cell Biology, Molecular Biology) including but not limited to reconstitution of signaling pathways in cell-free systems, protein fraction and purification, microarray and RNAi to accomplish that. We hope our work can deepen our understanding of NF-kB activation and provide novel pharmaceutical targets for the treatment of inflammatory diseases, viral infection and cancer.
We also just started to expand our work on ubiquitin function to other important and interesting areas such as human embryonic stem cells, germ cells and gamete biogenesis.
Any people interested in our work are strongly encouraged to contact us for potential training, employment and research cooperation opportunities.