Nucleoplasmic mobilization of NS stabilizes MDM2 and promotes G2/M transition and cell survival.
(A) In dividing interphase cells, NS is localized in the nucleolus (grey circle), while MDM2 resides in the nucleoplasm (yellow circle) and blocks the activities of p53 by ubiquitylation (Ub) and transcriptional inhibition. (B) The nucleoli are disassembled when exposed to drugs that trigger nucleolar stress or GTP depletion. In the NS-enriched cells (left panel), nucleoplasmic translocation of NS inhibits the p53’s activity by stabilizing MDM2 and by competing against L23 for MDM2 binding. In the NS-deficient cells (right panel), MDM2 is either sequestered in the nucleolus by L23 or degraded, leading to G2/M arrest and cell death. (C) Nucleolar disassembly during mitosis releases NS into the nucleoplasm/cytoplasm, allowing NS to bind and stabilize MDM2. Stabilized MDM2 inhibits p53’s functions and safeguards the proliferation and survival of continuously dividing cells. Mit, mitochondria; 26S, 26S-proteasome.