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

Autori
Velimezi, Georgia ; Liontos, Michalis ; Roumeliotis, Konstantinos Vougas Theodoros ; Bartkova, Jirina ; Sideridou, Maria ; Dereli-Oz, Ayguel : Kocylowski, Maciej ; Pateras, Ioannis S. ; Evangelou, Kostas ; Kotsinas, Athanassios ; Oršolić, Ines ; Bursać, Slađana ; Cokarić-Brdovčak, Maja ; Zoumpourlis, Vassilis ; Kletsas, Dimitris ; Papafotiou, George ; Klinakis, Apostolos ; Volarević, Siniša ; Gu, Wei ; Bartek, Jiri ; Halazonetis, Thanos D. ; Gorgoulis, Vassilis G.

Izvornik
Nature cell biology (1465-7392) 15 (2013); 967-977

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
ribosome biogenesis; ARF tumour suppressor; DNA damage

Sažetak
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, in a transcription-independent manner, ARF protein levels and activity. 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.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

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