title: Functional interplay between the DNA-damage-response kinase ATM and ARF tumour suppressor protein in human cancer.
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.
authors.affiliation: Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, 75 Mikras Asias Str, Athens, GR-11527, Greece.
authors.forename: Georgia
authors.initials: G
authors.lastname: Velimezi
authors.forename: Michalis
authors.initials: M
authors.lastname: Liontos
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Vougas
authors.forename: Theodoros
authors.initials: T
authors.lastname: Roumeliotis
authors.forename: Jirina
authors.initials: J
authors.lastname: Bartkova
authors.forename: Maria
authors.initials: M
authors.lastname: Sideridou
authors.forename: Ayguel
authors.initials: A
authors.lastname: Dereli-Oz
authors.forename: Maciej
authors.initials: M
authors.lastname: Kocylowski
authors.forename: Ioannis S
authors.initials: IS
authors.lastname: Pateras
authors.forename: Kostas
authors.initials: K
authors.lastname: Evangelou
authors.forename: Athanassios
authors.initials: A
authors.lastname: Kotsinas
authors.forename: Ines
authors.initials: I
authors.lastname: Orsolic
authors.forename: Sladana
authors.initials: S
authors.lastname: Bursac
authors.forename: Maja
authors.initials: M
authors.lastname: Cokaric-Brdovcak
authors.forename: Vassilis
authors.initials: V
authors.lastname: Zoumpourlis
authors.forename: Dimitris
authors.initials: D
authors.lastname: Kletsas
authors.forename: George
authors.initials: G
authors.lastname: Papafotiou
authors.forename: Apostolos
authors.initials: A
authors.lastname: Klinakis
authors.forename: Sinisa
authors.initials: S
authors.lastname: Volarevic
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.forename: Thanos D
authors.initials: TD
authors.lastname: Halazonetis
authors.forename: Vassilis G
authors.initials: VG
authors.lastname: Gorgoulis
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002352:Carrier Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D000072379:NIMA-Related Kinases; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D012270:Ribosomes / Q000378:metabolism; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025803:Tumor Suppressor Protein p14ARF; C530813:TRIP12 protein, human; D044767:Ubiquitin-Protein Ligases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; C089441:NEK2 protein, human; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases; D020823:ADP-Ribosylation Factor 1