title: Cytokinetic Failure-induced Tetraploidy Develops into Aneuploidy, Triggering Skin Aging in Phosphovimentin-deficient Mice.
abstract: Tetraploidy, a state in which cells have doubled chromosomal sets, is observed in ∼20% of solid tumors and is considered to frequently precede aneuploidy in carcinogenesis. Tetraploidy is also detected during terminal differentiation and represents a hallmark of aging. Most tetraploid cultured cells are arrested by p53 stabilization. However, the fate of tetraploid cells in vivo remains largely unknown. Here, we analyze the ability to repair wounds in the skin of phosphovimentin-deficient (VIM(SA/SA)) mice. Early into wound healing, subcutaneous fibroblasts failed to undergo cytokinesis, resulting in binucleate tetraploidy. Accordingly, the mRNA level of p21 (a p53-responsive gene) was elevated in a VIM(SA/SA)-specific manner. Disappearance of tetraploidy coincided with an increase in aneuploidy. Thereafter, senescence-related markers were significantly elevated in VIM(SA/SA) mice. Because our tetraploidy-prone mouse model also exhibited subcutaneous fat loss at the age of 14 months, another premature aging phenotype, our data suggest that following cytokinetic failure, a subset of tetraploid cells enters a new cell cycle and develops into aneuploid cells in vivo, which promote premature aging.
authors.affiliation: From the Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya 464-8681.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: From the Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya 464-8681, the Departments of Cellular Oncology and.
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Goto
authors.affiliation: From the Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya 464-8681.
authors.forename: Akihito
authors.initials: A
authors.lastname: Inoko
authors.affiliation: From the Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya 464-8681, the Department of Oral and Maxillofacial Surgery, School of Dentistry, Aichi Gakuin University, Nagoya 466-8550, and.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Makihara
authors.affiliation: Pathology, Nagoya University Graduate School of Medicine, Nagoya 466-8550.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Enomoto
authors.affiliation: the Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan.
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Horimoto
authors.affiliation: From the Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya 464-8681.
authors.forename: Makoto
authors.initials: M
authors.lastname: Matsuyama
authors.affiliation: the Department of Oral and Maxillofacial Surgery, School of Dentistry, Aichi Gakuin University, Nagoya 466-8550, and.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kurita
authors.affiliation: From the Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya 464-8681.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Izawa
authors.affiliation: From the Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya 464-8681, the Departments of Cellular Oncology and minagaki@aichi-cc.jp.
authors.forename: Masaki
authors.initials: M
authors.lastname: Inagaki
mesh_terms: D000782:Aneuploidy; D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D048749:Cytokinesis; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D007124:Immunoenzyme Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008938:Mitosis / Q000502:physiology; D010766:Phosphorylation; D015595:Skin Aging / Q000473:pathology*; D050151:Subcutaneous Fat / Q000378:metabolism / Q000473:pathology*; D057891:Tetraploidy; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014746:Vimentin / Q000502:physiology*; D014945:Wound Healing
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D014746:Vimentin
keywords: aging; aneuploidy; cytokinesis; intermediate filament; phosphorylation; skin; tetraploidy
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