title: p14ARF activates a Tip60-dependent and p53-independent ATM/ATR/CHK pathway in response to genotoxic stress.
abstract: p14ARF is a tumor suppressor that controls a well-described p53/Mdm2-dependent checkpoint in response to oncogenic signals. Here, new insights into the tumor-suppressive function of p14ARF are provided. We previously showed that p14ARF can induce a p53-independent G2 cell cycle arrest. In this study, we demonstrate that the activation of ATM/ATR/CHK signaling pathways contributes to this G2 checkpoint and highlight the interrelated roles of p14ARF and the Tip60 protein in the initiation of this DNA damage-signaling cascade. We show that Tip60 is a new direct p14ARF binding partner and that its expression is upregulated and required for ATM/CHK2 activation in response to p14ARF. Strikingly, both p14ARF and Tip60 products accumulate following a cell treatment with alkylating agents and are absolutely required for ATM/CHK2 activation in this setting. Moreover, and consistent with p14ARF being a determinant of CHK2 phosphorylation in lung carcinogenesis, a strong correlation between p14ARF and phospho-CHK2 (Thr68) protein expression is observed in human lung tumors (P < 0.00006). Overall, these data point to a novel regulatory pathway that mediates the p53-independent negative-cell-growth control of p14ARF. Inactivation of this pathway is likely to contribute to lung carcinogenesis.
authors.affiliation: Groupe de Recherche sur le Cancer du Poumon, INSERM U578, Institut Albert Bonniot, 38706 La Tronche Cedex, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Eymin
authors.forename: Paule
authors.initials: P
authors.lastname: Claverie
authors.forename: Caroline
authors.initials: C
authors.lastname: Salon
authors.forename: Camille
authors.initials: C
authors.lastname: Leduc
authors.forename: Edwige
authors.initials: E
authors.lastname: Col
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brambilla
authors.forename: Saadi
authors.initials: S
authors.lastname: Khochbin
authors.forename: Sylvie
authors.initials: S
authors.lastname: Gazzeri
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D019556:COS Cells; D002110:Caffeine / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D064447:Checkpoint Kinase 2; D002522:Chlorocebus aethiops; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D016195:G2 Phase; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D000074443:Lysine Acetyltransferase 5; D009153:Mutagens / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009153:Mutagens; D009363:Neoplasm Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D002110:Caffeine; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases