This study provides the following insight; the elucidation of a novel mechanism by which NPM1 recruits Mdm2 to promote the ubiquitin-mediated degradation of p53, which results in the inhibition of the p53-related signaling pathway both in vitro and in vivo.

NPM1 stabilizes both TP53 and MDM2, the TP53 negative regulator, hence modulating cellular growth suppression through p53-dependent and independent mechanisms. Loss of NPM1 could affect levels of TP53, leading to oncogenic transformation.

May 15, 2023 · Mechanistic analyses revealed that the E3 ubiquitin ligase Mdm2 was recruited by NPM1 to induce the ubiquitination-mediated proteasomal degradation of p53. Ultimately, knockdown of NPM1 suppressed the stemness and EMT signals.

Upon cellular stress, NPM1 moves from the nucleolus to the nucleoplasm where it binds MDM2, inhibiting MDM2 mediated degradation of TP53, leading to an increase in TP53 activity which results in cell cycle arrest or apoptosis.

Dec 22, 2016 · NPM1 has an important role in maintaining p53 stability 27 and has an inhibitory effect on the expression of MDM2 (Supplementary Figure S6), 28 a major negative regulator of p53.

Dec 17, 2024 · In this review, we focus on the functions of the native NPM1 protein and how its mutant contributes to promote and maintain acute myeloid leukemia (AML).

Jan 23, 2017 · In this review, we discuss the many functions of NPM1, the consequence of mutations in NPM1 and possible mechanisms through which mutations lead to leukemogenesis.

Jan 1, 2023 · NPM1 and p14ARF each bind MDM2, stabilizing p53. NPM1 also activates caspase-2 via the PIDDosome. These pathways result in cell cycle arrest, senescence, or apoptosis.

Jan 10, 2019 · The NPM1-MDM2 interaction is particularly enhanced upon NPM1 nuclear relocalization following nucleolar stress and this pathway is currently being investigated for the development of novel therapies in NPM1-mutated AML through nucleolar stress induction .

Mar 10, 2014 · Our manuscript describes that the N-terminal domain of NPM1 (Npm-N) exhibits phosphorylation-dependent structural polymorphism along a broad conformational landscape between two extreme states: a stable, folded pentamer and a globally disordered monomer.