REGgamma modulates p53 activity by regulating its cellular localization.

TitleREGgamma modulates p53 activity by regulating its cellular localization.
Publication TypeJournal Article
Year of Publication2010
AuthorsLiu, J, Yu, G, Zhao, Y, Zhao, D, Wang, Y, Wang, L, Liu, J, Li, L, Zeng, Y, Dang, Y, Wang, C, Gao, G, Long, W, Lonard, DM, Qiao, S, Tsai, M-J, Zhang, B, Luo, H, Li, X
JournalJournal of Cell Science
Volume123
IssuePt 23
Pagination4076-84
Date Published2010 Dec 1
ISSN1477-9137
KeywordsActive Transport, Cell Nucleus, Animals, Autoantigens, Cell Line, Tumor, Cell Nucleus, Cytoplasm, Female, Humans, Mice, Mice, Inbred BALB C, Mice, Knockout, Proteasome Endopeptidase Complex, Protein Binding, Protein Multimerization, Protein Transport, Random Allocation, Tumor Suppressor Protein p53, Ubiquitination
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.

DOI10.1242/jcs.067405
Alternate JournalJ. Cell. Sci.
PubMed ID21084564
PubMed Central IDPMC2987440
Grant List1R01CA131914 / CA / NCI NIH HHS / United States
92214-1 / / Canadian Institutes of Health Research / Canada
R01 CA131914 / CA / NCI NIH HHS / United States