title: Onset of quiescence following p53 mediated down-regulation of H2AX in normal cells.
abstract: Normal cells, both in vivo and in vitro, become quiescent after serial cell proliferation. During this process, cells can develop immortality with genomic instability, although the mechanisms by which this is regulated are unclear. Here, we show that a growth-arrested cellular status is produced by the down-regulation of histone H2AX in normal cells. Normal mouse embryonic fibroblast cells preserve an H2AX diminished quiescent status through p53 regulation and stable-diploidy maintenance. However, such quiescence is abrogated under continuous growth stimulation, inducing DNA replication stress. Because DNA replication stress-associated lesions are cryptogenic and capable of mediating chromosome-bridge formation and cytokinesis failure, this results in tetraploidization. Arf/p53 module-mutation is induced during tetraploidization with the resulting H2AX recovery and immortality acquisition. Thus, although cellular homeostasis is preserved under quiescence with stable diploidy, tetraploidization induced under growth stimulation disrupts the homeostasis and triggers immortality acquisition.
authors.affiliation: Division of Genome Stability Research, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Atsumi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Fujimori
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Fukuda
authors.forename: Aki
authors.initials: A
authors.lastname: Inase
authors.forename: Keitaro
authors.initials: K
authors.lastname: Shinohe
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Yoshioka
authors.forename: Mima
authors.initials: M
authors.lastname: Shikanai
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ichijima
authors.forename: Junya
authors.initials: J
authors.lastname: Unno
authors.forename: Shuki
authors.initials: S
authors.lastname: Mizutani
authors.forename: Naoto
authors.initials: N
authors.lastname: Tsuchiya
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hippo
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakagama
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Masutani
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Teraoka
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yoshioka
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D003603:Cytotoxins / Q000494:pharmacology; D004171:Diploidy; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D042822:Genomic Instability; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011123:Polyploidy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D009353:Zinostatin / Q000494:pharmacology
chemical_list: D003603:Cytotoxins; D006657:Histones; D016159:Tumor Suppressor Protein p53; D009353:Zinostatin; C475961:gamma-H2AX protein, mouse