title: Arf and p53 act as guardians of a quiescent cellular state by protecting against immortalization of cells with stable genomes.
abstract: Normal cells undergo a growth-arrested status that is produced by p53-dependent down-regulation of histone H2AX. Immortality is developed after abrogation of the H2AX-diminished state, which is associated with genomic instability (often with tetraploidy) and the induction of mutations in either the Arf or p53 gene. However, the role of Arf in control of H2AX expression and genome stability is still unclear. Here, we show that both Arf and p53 are required for the down-regulation of H2AX and formation of the growth-arrested state. Wild-type (WT) mouse embryonic fibroblasts (MEFs) subjected to tetraploidization with DNA lesions did not undergo mitotic catastrophe-associated cell death and stayed in a growth-arrested state, until immortality was attained with mutations in the Arf/p53 module and recovery of H2AX expression. Whereas tetraploidization was essential for immortalization of WT MEFs, this event was not required for immortalization of MEFs containing mutations in Arf/p53 and these cells still underwent mitotic catastrophe-associated cell death. Thus, WT MEFs are protected from immortalization with genome stability, which is abrogated with tetraploidization and mutation of either Arf or p53.
authors: Division of Genome Stability Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors: Tomoyuki
authors: T
authors: Osawa
authors: Yuko
authors: Y
authors: Atsumi
authors: Eiji
authors: E
authors: Sugihara
authors: Hideyuki
authors: H
authors: Saya
authors: Masamoto
authors: M
authors: Kanno
authors: Fumio
authors: F
authors: Tashiro
authors: Mitsuko
authors: M
authors: Masutani
authors: Ken-Ichi
authors: K
authors: Yoshioka
mesh_terms: D016475:3T3 Cells; D000818:Animals; D059447:Cell Cycle Checkpoints; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000502:physiology*; D004171:Diploidy; D042822:Genomic Instability; D006657:Histones / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D057891:Tetraploidy; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D006657:Histones; D016159:Tumor Suppressor Protein p53; C417743:Cdkn2a protein, mouse; C475961:gamma-H2AX protein, mouse