NORE1A is a Ras senescence effector that controls the apoptotic/senescent balance of p53 via HIPK2

Abstract

NORE1A is a Ras senescence effector that modulates HIPK2-dependent posttranslational modifications of p53.

The discovery of a novel, Ras-mediated NORE1A/PMLIV tumor suppressor complex.

“…In 2015, Donninger et al found that NORE1A over-expression induces senescence at levels comparable to those induced by activated Ras, and suppression of NORE1A both impairs senescence and enhances Ras-mediated transformation [17]. This correlates with Calvisi's finding that NORE1A expression in primary human tumors correlates with the expression of markers of senescence [123].…”

“…Phosphorylation at residue Ser46 by HIPK2 promotes apoptosis, but HIPK2 can also recruit acetyltransferases to acetylate p53 at specific lysine residues to promote pro-senescence effects (Reviewed in [152]). NORE1A promotes the scaffolding of HIPK2 to p53, resulting in the suppression of Ser46 phosphorylation of p53 and the enhancement of p53 acetylation at lysine residues 382 and 320, which drive p53-dependent senescence [17]. Without the presence of p53, however, NORE1A still retained some ability to induce senescence, suggesting that NORE1A regulates senescence through a multifaceted process [17].…”

“…PML NBs are centers of protein post-translational modifications, and NORE1A has recently been shown to play a role in protein acetylation-specifically, the acetylation of p53-phosphorylation, and ubiquitination [16,17,21,23]. Therefore, Ras's promotion of the interaction of NORE1A with PML, specifically the isoform PMLIV, could provide a novel mechanism by which Ras regulates protein function through both protein localization and post-translational modifications.…”

“…and scaffolds p53 to the kinase HIPK2, providing the mechanistic basis for the initial findings of Calvisi in 2009 [17,123]. HIPK2 can mediate post-translational modifications of p53 at various residues to mediate different functions.…”

“…Ras stimulation, NORE1A can promote post-translational modifications of both the p53 and Rb tumor suppressors by binding to mediators of p53 acetylation and Rb phosphorylation [16,17].…”