title: Necessary and sufficient role for a mitosis skip in senescence induction.
abstract: Senescence is a state of permanent growth arrest and is a pivotal part of the antitumorigenic barrier in vivo. Although the tumor suppressor activities of p53 and pRb family proteins are essential for the induction of senescence, molecular mechanisms by which these proteins induce senescence are still not clear. Using time-lapse live-cell imaging, we demonstrate here that normal human diploid fibroblasts (HDFs) exposed to various senescence-inducing stimuli undergo a mitosis skip before entry into permanent cell-cycle arrest. This mitosis skip is mediated by both p53-dependent premature activation of APC/C(Cdh1) and pRb family protein-dependent transcriptional suppression of mitotic regulators. Importantly, mitotic skipping is necessary and sufficient for senescence induction. p16 is only required for maintenance of senescence. Analysis of human nevi also suggested the role of mitosis skip in in vivo senescence. Our findings provide decisive evidence for the molecular basis underlying the induction and maintenance of cellular senescence.
authors.affiliation: Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Johmura
authors.affiliation: Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Shimada
authors.affiliation: Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Misaki
authors.affiliation: Department of Experimental Pathology and Tumor Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Naiki-Ito
authors.affiliation: Subteam for Manipulation of Cell Fate, RIKEN BioResource Center, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyoshi
authors.affiliation: Department of Cognitive Brain Science, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8511, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Motoyama
authors.affiliation: Division of Cancer Biology, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Ohtani
authors.affiliation: Division of Cancer Biology, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Hara
authors.affiliation: Department of Geriatric and Environmental Dermatology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Motoki
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Geriatric and Environmental Dermatology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Akimichi
authors.initials: A
authors.lastname: Morita
authors.affiliation: Department of Experimental Pathology and Tumor Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. Electronic address: mkt-naka@med.nagoya-cu.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakanishi
mesh_terms: D059447:Cell Cycle Checkpoints; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008938:Mitosis / Q000502:physiology*; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology; D059008:Time-Lapse Imaging; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53