title: Ribosomal protein S7 regulates arsenite-induced GADD45α expression by attenuating MDM2-mediated GADD45α ubiquitination and degradation.
abstract: The stress-responding protein, GADD45α, plays important roles in cell cycle checkpoint, DNA repair and apoptosis. In our recent study, we demonstrate that GADD45α undergoes a dynamic ubiquitination and degradation in vivo, which process can be blocked by the cytotoxic reagent, arsenite, resulting in GADD45α accumulation to activate JNKs cell death pathway, thereby revealing a novel mechanism for the cellular GADD45α functional regulation. But the factors involved in GADD45α stability modulations are unidentified. Here, we demonstrated that MDM2 was an E3 ubiquitin ligase for GADD45α. One of MDM2-binding partner, ribosomal protein S7, interacted with and stabilized GADD45α through preventing the ubiquitination and degradation of GADD45α mediated by MDM2. This novel function of S7 is unrelated to p53 but seems to depend on S7/MDM2 interaction, for the S7 mutant lacking MDM2-binding ability lost its function to stabilize GADD45α. Further investigations indicated that arsenite treatment enhanced S7-MDM2 interaction, resulting in attenuation of MDM2-dependent GADD45α ubiquitination and degradation, thereby leading to GADD45α-dependent cell death pathway activation. Silencing S7 expression suppressed GADD45α-dependent cytotoxicity induced by arsenite. Our findings thus identify a novel function of S7 in control of GADD45α stabilization under both basal and stress conditions and its significance in mediating arsenite-induced cellular stress.
authors.affiliation: Department of Pathophysiology, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, PR China.
authors.forename: Ming
authors.initials: M
authors.lastname: Gao
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Li
authors.forename: Wen
authors.initials: W
authors.lastname: Dong
authors.forename: Rui
authors.initials: R
authors.lastname: Jin
authors.forename: Hanghang
authors.initials: H
authors.lastname: Ma
authors.forename: Pingxun
authors.initials: P
authors.lastname: Yang
authors.forename: Meiru
authors.initials: M
authors.lastname: Hu
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Yi
authors.initials: Y
authors.lastname: Hao
authors.forename: Shengtao
authors.initials: S
authors.lastname: Yuan
authors.forename: Junjian
authors.initials: J
authors.lastname: Huang
authors.forename: Lun
authors.initials: L
authors.lastname: Song
mesh_terms: D017209:Apoptosis; D018053:Arsenites / Q000633:toxicity*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D055550:Protein Stability; D059748:Proteolysis / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D012269:Ribosomal Proteins / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects; D000097642:GADD45 Proteins
chemical_list: D018053:Arsenites; D018797:Cell Cycle Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D012269:Ribosomal Proteins; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C037442:ribosomal protein S7; C015001:arsenite
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