Nucleoplasmic mobilization of nucleostemin stabilizes MDM2 and promotes G2-M progression and cell survival

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Abstract
Nucleolar disassembly occurs during mitosis and nucleolar stress, releasing several MDM2-interactive proteins residing in the nucleolus that share the common activity of p53 stabilization. Here, we demonstrate that mobilization of nucleostemin, a nucleolar protein enriched in cancer and stem cells, has the opposite role of stabilizing MDM2 and suppressing p53 functions. Our results show that nucleostemin increases the protein stability and nucleoplasmic retention of MDM2, and competes with L23 for MDM2 binding. These activities were significantly elevated when nucleostemin is released into the nucleoplasm by mutations that abolish its nucleolar localization or by chemotherapeutic agents that disassemble the nucleoli. Nucleostemin depletion decreases MDM2 protein, increases transcription activity without affecting the level of p53 protein, and triggers G2-M arrest and cell death in U2OS cells but not in H1299 cells. This work reveals that nucleoplasmic relocation of nucleostemin during nucleolar disassembly safeguards the G2-M transit and survival of continuously dividing cells by MDM2 stabilization and p53 inhibition.