The Physiology And Pathology Study Of REG γ

The proteasome system is one of the most import protein degradation systems. It plays a key role in the cellular processes such as cell cycle, transcription, cell signaling, cell death and immune responses.If the function of proteasome is abnormal, cellular proteins can not be degradated properly and the cell function could be in disorder. REGγis one of the activators of proteasome, it can specifically bind to and activate the 20S proteasome and degradate proteins in ATP and ubiquitin independent way. Now, the REG family contains three members:REGa,REGβand REGγ.REG Y forms a homoheptamer, which contains seven 28KD subunits.Now cancer is the leading cause of death wordwide. lung, colon and thyroid cancers are among the leading causes of deaths each year. The mechanisms of cancers are complex, while bearing a common feature that cell cycle or cell growth is out of control. Studies in our lab find that REG Y can promote degradation of p53 by acting as a co-factor to promote MDM2-mediated p53 ubiquitination. As we know that p53 is an important hinge which plays a key role in cell growth, differentiation and death. It integrates many different signals for cell growth and controls cell fate. We know that p21 is a cyclin-dependent kinase inhibitor. It can inhibit apoptosis and induce cell cycle arrest. REGγ-proteasm can directly degrade p21.Given the potential role of REG Y in the regulation of cell cycle, we initiated this project to explore additional physiological function of REG Y and its pathological implications.To achieve our goal, we used immunohistochemistry to study the expression of REG Y in mice tissues and some tissue array samples from human. Then we analyzed the expression of REG Y in human colon, lung and thyroid cancers.We further explore the mechanisms of REGγmediated regulation of p53.We performed systematic analysis of REGy gene expression in 20 different tissues from mice, followed by validation of protein expression in mouse tissues and bioinformatic analysis of REGy gene expression profiles in selected human tissues. Comparative analysis of REGy distribution in different tissues from wild type and REGy knockout mice indicates that REGy is present in many tissues and is specifically expressed in some cell types. The highest expression of REGy is in the testis and has unique expression features in a subset of neurons, including retinal ganglion cells and Purkinje cells.It is also expressed in reproductive and gastro-intestinal organs.Significant inverse correlation has been observed in multiple tissues and cell types.These expressed patterns suggest potentially important functions for REGy in the nervous system, reproductive system and in cells with proliferative capacity. Consistent with the importance of its expression in reproductive tissue, REGy deficiency results in dose-dependent reduction in litter size.