Ribosomal protein S7 regulates arsenite-induced GADD45  expression by attenuating MDM2-mediated GADD45  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.

Nutlin-3a Efficacy in Sarcoma Predicted by Transcriptomic and Epigenetic Profiling

“…Recently, it has been reported that MDM2 functions as an E3 ubiquitin ligase for GADD45A. Enhanced association between MDM2 and RPS7 following arsenite treatment attenuated MDM2-mediated GADD45A ubiquitination, resulting in GADD45A protein stabilization and apoptosis (41). Interestingly, our microarray analysis identified RPS27L, a direct TP53 target, that modulates cell fate in response to genotoxic stress (42), to be upregulated only in those sarcomas in which robust apoptotic responses were observed.…”

Ribosomal Proteins and Human Diseases: Pathogenesis, Molecular Mechanisms, and Therapeutic Implications

“…S7 forms a complex with GADD45α (growth arrest and DNA damage inducible gene 45α), which regulates DNA repair, cell cycle checkpoints, and apoptosis. S7 interacts with both MDM2 and GADD45α, protecting GADD45α from MDM2‐mediated ubiquitination and degradation . However, S7 mutants lacking the ability to bind MDM2 do not stabilize GADD45α, indicating the importance of the RP–MDM2 interplay (Fig.…”

“…However, S7 mutants lacking the ability to bind MDM2 do not stabilize GADD45α, indicating the importance of the RP–MDM2 interplay (Fig. H) …”

The role of ribosomal proteins in the regulation of cell proliferation, tumorigenesis, and genomic integrity

“…Activated p53 then transactivates its downstream targets to induce growth arrest and apoptosis to block tumorigenesis. (Adilakshmi and Laine, 2002;Bai et al, 2014;Barlow et al, 2010a;He and Sun, 2007;Jang et al, 2012a;Jeon et al, 2008;Khanna et al, 2003;Li et al, 2010;Naora et al, 1998;Neumann and Krawinkel, 1997;Russo et al, 2013;Takagi et al, 2005;Wu et al, 2012;Yang et al, 2012;Zhu et al, 2009) Cell cycle S3, S5, S6, S7, S14, S15, S19, S20, S25, S26, S27, S27L, S27a, L3, L5, L6, L7, L11, L13, L23, L26, L31, L34, L37, L41 (Cui et al, 2014;Daftuar et al, 2013;Dai et al, , 2007bGao et al, 2013;Gou et al, 2010;Iadevaia et al, 2010;Kobayashi et al, 2006;Maruyama et al, 2014;Matragkou et al, 2008;Moorthamer and Chaudhuri, 1999;Neumann and Krawinkel, 1997;Russo et al, 2013;Sun et al, 2011;Takagi et al, 2005;Wang et al, 2011a;Wanzel et al, 2008;Xiong et al, 2011;Zhang et al, 2013Zhang et al, , 2015Zhou et al, 2013a) Cell proliferation S6, S9, S13, S14, S15a, S24, S27, L6, L8, L11, L15, L17, L26, L29, L31, L34, L36a (Dai et al, 2007a;Gou et al, 2010Kim et al, 2004;Li et al, 2010…”