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.

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.

In unstressed cells, p14 ARF and NPM1 form a dimer in the nucleoli, allowing MDM2 to target p53 for proteasomal degradation. Following a stress, such as DNA damages, p14 ARF and NPM1 dissociate and relocate to the nucleus were they sequester MDM2, leading to the stabilization and activation of p53. p53 then induces the transcription of various ...

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.

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.

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 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.

Dec 22, 2016 · Mechanistically, we show that NPM1 downregulation by P-STAT5 is mediated by impairing the BRCA1-BARD1 ubiquitin ligase, which controls the stability of NPM1. In turn, decreased NPM1 levels led to suppression of p53 expression, resulting in enhanced cell survival.

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.

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.