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

Article Article scientifique Article Functional interplay between the DNA-damage-response kinase ATM and ARF tumour suppressor protein in human cancer eng 2013-07-14 2013-07-14 author Velimezi Georgia author Liontos Michalis author Vougas Konstantinos author Roumeliotis Theodoros author Bartkova Jirina author Sideridou Maria author Dereli-Oz Ayguel author Kocylowski Maciej 683960 author Pateras Ioannis S. author Evangelou Kostas author Kotsinas Athanassios author Orsolic Ines author Bursac Sladana author Cokaric-Brdovcak Maja author Zoumpourlis Vassilis author Kletsas Dimitris author Papafotiou George author Klinakis Apostolos author Volarevic Sinisa author Gu Wei author Bartek Jiri author Halazonetis Thanos 641033 Département de biologie moléculaire et cellulaire (MOCEL) author Gorgoulis Vassilis G. 967-977 10.1038/ncb2795 23851489 1465-7392 https://www.nature.com/articles/ncb2795 <p>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.</p> Dewey 570 43 Département de biologie moléculaire 161 false Nature cell biology 15 8 84c3dbda-8c3b-40bb-9c76-0e80bd0d4217 Article (Published version) Restricted Article-scientifique-from-crossref.pdf 5936396 application/pdf 3fe29c437182a8e207a4034810b4d2d69e6f8b4a1638c86def9370d8d2e517aa restrictedAccess Faculté des sciences / Section de biologie / Département de biologie moléculaire

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RNF168-mediated H2AX ubiquitination recruits 53BP1 to DNA double-strand breaks		2014	997	10
Functional interplay between the DNA-damage-response kinase ATM and ARF tumour suppressor protein in human cancer	Nature cell biology	2013	70	0

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