Functional interplay between the DNA-damage-response kinase ATM and ARF tumour suppressor protein in human cancer

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

doi:10.1038/ncb2795

Functional interplay between the DNA-damage-response kinase ATM and ARF tumour suppressor protein in human cancer

Nat Cell Biol. 2013 Aug;15(8):967-77. doi: 10.1038/ncb2795. Epub 2013 Jul 14.

Affiliation

¹ Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, 75 Mikras Asias Str, Athens, GR-11527, Greece.

PMID: 23851489
DOI: 10.1038/ncb2795

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ADP-Ribosylation Factor 1 / genetics
ADP-Ribosylation Factor 1 / metabolism*
Animals
Ataxia Telangiectasia Mutated Proteins
Carrier Proteins / metabolism
Cell Cycle / physiology
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism*
Cell Line
Cell Line, Tumor
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Gene Expression Regulation, Neoplastic
HeLa Cells
Humans
Male
Mice
NIMA-Related Kinases
Neoplasms / enzymology
Neoplasms / pathology
Neoplasms / physiopathology*
Phosphorylation
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Protein Stability
Ribosomes / metabolism
Signal Transduction
Transplantation, Heterologous
Tumor Suppressor Protein p14ARF / genetics
Tumor Suppressor Protein p14ARF / metabolism*
Ubiquitin-Protein Ligases / metabolism

Substances

Carrier Proteins
Cell Cycle Proteins
DNA-Binding Proteins
Tumor Suppressor Protein p14ARF
TRIP12 protein, human
Ubiquitin-Protein Ligases
ATM protein, human
Ataxia Telangiectasia Mutated Proteins
Atm protein, mouse
NEK2 protein, human
NIMA-Related Kinases
Protein Serine-Threonine Kinases
ADP-Ribosylation Factor 1