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

The Journal of Cell Biology
Howard DonningerGeoffrey J Clark

Abstract

The Ras oncoprotein is a key driver of cancer. However, Ras also provokes senescence, which serves as a major barrier to Ras-driven transformation. Ras senescence pathways remain poorly characterized. NORE1A is a novel Ras effector that serves as a tumor suppressor. It is frequently inactivated in tumors. We show that NORE1A is a powerful Ras senescence effector and that down-regulation of NORE1A suppresses senescence induction by Ras and enhances Ras transformation. We show that Ras induces the formation of a complex between NORE1A and the kinase HIPK2, enhancing HIPK2 association with p53. HIPK2 is a tumor suppressor that can induce either proapoptotic or prosenescent posttranslational modifications of p53. NORE1A acts to suppress its proapoptotic phosphorylation of p53 but enhance its prosenescent acetylation of p53. Thus, we identify a major new Ras signaling pathway that links Ras to the control of specific protein acetylation and show how NORE1A allows Ras to qualitatively modify p53 function to promote senescence.

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Citations

Jan 28, 2016·Chemical Reviews·Shaoyong LuJian Zhang
Dec 23, 2015·Cancers·Hiroaki IwasaYutaka Hata
Mar 22, 2016·Cancers·Thibaut BarnoudHoward Donninger
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Methods Mentioned

BETA
acetylation
transfections
Immunoprecipitation
transfection
PCR

Software Mentioned

Origene
ImageJ
Quantity One
ProSci
GraphPad Prism

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