title: REGgamma modulates p53 activity by regulating its cellular localization.
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.
authors.affiliation: Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Guowu
authors.initials: G
authors.lastname: Yu
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Dengpan
authors.initials: D
authors.lastname: Zhao
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Jiang
authors.initials: J
authors.lastname: Liu
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Zeng
authors.forename: Yongyan
authors.initials: Y
authors.lastname: Dang
authors.forename: Chuangui
authors.initials: C
authors.lastname: Wang
authors.forename: Guang
authors.initials: G
authors.lastname: Gao
authors.forename: Weiwen
authors.initials: W
authors.lastname: Long
authors.forename: David M
authors.initials: DM
authors.lastname: Lonard
authors.forename: Shanlou
authors.initials: S
authors.lastname: Qiao
authors.forename: Ming-Jer
authors.initials: MJ
authors.lastname: Tsai
authors.forename: Bianhong
authors.initials: B
authors.lastname: Zhang
authors.forename: Honglin
authors.initials: H
authors.lastname: Luo
authors.forename: Xiaotao
authors.initials: X
authors.lastname: Li
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D021381:Protein Transport; D011897:Random Allocation; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D001324:Autoantigens; C099558:Ki antigen; D016159:Tumor Suppressor Protein p53; D046988:Proteasome Endopeptidase Complex