Περίληψη:
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. © 2013 Macmillan Publishers Limited. All rights reserved.
Συγγραφείς:
Velimezi, G.
Liontos, M.
Vougas, K.
Roumeliotis, T.
Bartkova, J.
Sideridou, M.
Dereli-Oz, A.
Kocylowski, M.
Pateras, I.S.
Evangelou, K.
Kotsinas, A.
Orsolic, I.
Bursac, S.
Cokaric-Brdovcak, M.
Zoumpourlis, V.
Kletsas, D.
Papafotiou, G.
Klinakis, A.
Volarevic, S.
Gu, W.
Bartek, J.
Halazonetis, T.D.
Gorgoulis, V.G.
Λέξεις-κλειδιά:
ARF protein; ATM protein; messenger RNA; nucleophosmin; phosphoprotein phosphatase 1; protein kinase; protein Nek2A; protein ULF; short hairpin RNA; small interfering RNA; ubiquitin protein ligase E3; unclassified drug, advanced cancer; animal experiment; animal model; animal tissue; ARF gene; article; ATM gene; cancer cell culture; carcinogenesis; cell cycle progression; controlled study; DNA damage; female; gene; gene expression regulation; human; human cell; human tissue; in vitro study; in vivo study; intracellular signaling; lung non small cell cancer; malignant neoplastic disease; nonhuman; priority journal; protein degradation; protein depletion; protein expression; protein phosphorylation; protein protein interaction; protein stability; transcription regulation; tumor xenograft, ADP-Ribosylation Factor 1; Animals; Carrier Proteins; Cell Cycle; Cell Cycle Proteins; Cell Line; Cell Line, Tumor; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; Male; Mice; Neoplasms; Phosphorylation; Protein Stability; Protein-Serine-Threonine Kinases; Ribosomes; Signal Transduction; Transplantation, Heterologous; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases
