Functional Interplay Between the DNA-damage-response Kinase ATM and ARF Tumour Suppressor Protein in Human Cancer

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2013 Jul 16

PMID 23851489

Citations 76

Authors

Georgia Velimezi

Michalis Liontos

Konstantinos Vougas

Theodoros Roumeliotis

Jirina Bartkova

Maria Sideridou

Ayguel Dereli-Oz

Maciej Kocylowski

Ioannis S Pateras

Kostas Evangelou

Athanassios Kotsinas

Ines Orsolic

Sladana Bursac

Maja Cokaric-Brdovcak

Vassilis Zoumpourlis

Dimitris Kletsas

George Papafotiou

Apostolos Klinakis

Sinisa Volarevic

Wei Gu

Jiri Bartek

Thanos D Halazonetis

Vassilis G Gorgoulis

Affiliations

Soon will be listed here.

Abstract

The DNA damage response (DDR) pathway and ARF function as barriers to cancer development. Although commonly regarded as operating independently of each other, some studies proposed that ARF is positively regulated by the DDR. Contrary to either scenario, we found that in human oncogene-transformed and cancer cells, ATM suppressed ARF protein levels and activity in a transcription-independent manner. Mechanistically, ATM activated protein phosphatase 1, which antagonized Nek2-dependent phosphorylation of nucleophosmin (NPM), thereby liberating ARF from NPM and rendering it susceptible to degradation by the ULF E3-ubiquitin ligase. In human clinical samples, loss of ATM expression correlated with increased ARF levels and in xenograft and tissue culture models, inhibition of ATM stimulated the tumour-suppressive effects of ARF. These results provide insights into the functional interplay between the DDR and ARF anti-cancer barriers, with implications for tumorigenesis and treatment of advanced tumours.

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