[Show abstract][Hide abstract] ABSTRACT: Recent studies suggest a role of the proteasome activator, REGγ, in cancer progression. Since there are limited numbers of known REGγ targets, it is not known which cancers and pathways are associated with REGγ.
REGγ protein expressions in four different cancers were investigated by immunohistochemistry (IHC) analysis. Following NCBI Gene Expression Omnibus (GEO) database search, microarray platform validation, differential expressions of REGγ in corresponding cancers were statistically analyzed. Genes highly correlated with REGγ were defined based on Pearson's correlation coefficient. Functional links were estimated by Ingenuity Core analysis. Finally, validation was performed by RT-PCR analysis in established cancer cell lines and IHC in human colon cancer tissues
Here, we demonstrate overexpression of REGγ in four different cancer types by micro-tissue array analysis. Using meta-analysis of publicly available microarray databases and biological studies, we verified elevated REGγ gene expression in the four types of cancers and identified genes significantly correlated with REGγ expression, including genes in p53, Myc pathways, and multiple other cancer-related pathways. The predicted correlations were largely consistent with quantitative RT-PCR analysis.
This study provides us novel insights in REGγ gene expression profiles and its link to multiple cancer-related pathways in cancers. Our results indicate potentially important pathogenic roles of REGγ in multiple cancer types and implicate REGγ as a putative cancer marker.
[Show abstract][Hide abstract] ABSTRACT: The proteasome activator REGγ mediates a shortcut for the destruction of intact mammalian proteins. The biological roles of REGγ and the underlying mechanisms are not fully understood. Here we provide evidence that REGγ regulates cellular distribution of p53 by facilitating its multiple monoubiquitylation and subsequent nuclear export and degradation. We also show that inhibition of p53 tetramerization by REGγ might further enhance cytoplasmic relocation of p53 and reduce active p53 in the nucleus. Furthermore, multiple monoubiquitylation of p53 enhances its physical interaction with HDM2 and probably facilitates subsequent polyubiquitylation of p53, suggesting that monoubiquitylation can act as a signal for p53 degradation. Depletion of REGγ sensitizes cells to stress-induced apoptosis, validating its crucial role in the control of apoptosis, probably through regulation of p53 function. Using a mouse xenograft model, we show that REGγ knockdown results in a significant reduction of tumor growth, suggesting an important role for REGγ in tumor development. Our study therefore demonstrates that REGγ-mediated inactivation of p53 is one of the mechanisms involved in cancer progression.
[Show abstract][Hide abstract] ABSTRACT: The REGgamma proteasome has been reported as a shortcut to destruction of proteins. However, the physiological functions of REGgamma are largely unknown. To understand the potential biological roles of REGgamma associated with different tissues or cell types, we performed systematic analysis of REGgamma gene expression in 20 different tissues from mice, followed by validation of protein expression in mouse tissues and bioinformatic analysis of REGgamma gene expression profiles in selected human tissues. Comparative analysis of REGgamma distribution in different tissues from wild-type and REGgamma knockout mice indicates that REGgamma is present in many tissues and is specifically expressed in some cell types. The highest expression of REGgamma is in the testis and unique expression features of REGgamma are revealed in a subset of neurons, including retinal ganglion cells and Purkinje cells. It is also expressed in reproductive and gastro-intestinal organs. These expressed patterns suggest potentially important functions for REGgamma in the nervous system, reproductive system and in cells with proliferative capacity. Consistent with the importance of its expression in reproductive tissue, REGgamma deficiency results in dose-dependent reduction in litter size.