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Induction of apoptosis is pivotal for eliminating cells with damaged DNA or deregulated proliferation. We show that tumor suppressor ARF and ATM/ATR kinase pathways cooperate in the induction of apoptosis in response to elevated expression of c-myc, beta-catenin or human papilloma virus E7 oncogenes. Overexpression of oncogenes leads to the formation of phosphorylated H2AX foci, induction of Rad51 protein levels and ATM/ATR-dependent phosphorylation of p53. Inhibition of ATM/ATR kinases abolishes both induction of Rad51 and phosphorylation of p53, and remarkably reduces the level of apoptosis induced by co-expression of oncogenes and ARF. However, the induction of apoptosis is downregulated in p53-/- cells and does not depend on activities of ATM/ATR kinases, indicating that efficient induction of apoptosis by oncogene activation depends on coordinated action of ARF and ATM/ATR pathways in the regulation of p53.

Original publication




Journal article


Biochem biophys res commun

Publication Date





386 - 394


Animals, Apoptosis, Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins, Cell Line, Cyclin-Dependent Kinase Inhibitor p16, DNA-Binding Proteins, Fibroblasts, Humans, Mice, Oncogene Proteins, Oxidative Stress, Protein-Serine-Threonine Kinases, Tumor Suppressor Protein p14ARF, Tumor Suppressor Protein p53, Tumor Suppressor Proteins