title: A mitosis block links active cell cycle with human epidermal differentiation and results in endoreplication.
abstract: How human self-renewal tissues co-ordinate proliferation with differentiation is unclear. Human epidermis undergoes continuous cell growth and differentiation and is permanently exposed to mutagenic hazard. Keratinocytes are thought to arrest cell growth and cell cycle prior to terminal differentiation. However, a growing body of evidence does not satisfy this model. For instance, it does not explain how skin maintains tissue structure in hyperproliferative benign lesions. We have developed and applied novel cell cycle techniques to human skin in situ and determined the dynamics of key cell cycle regulators of DNA replication or mitosis, such as cyclins E, A and B, or members of the anaphase promoting complex pathway: cdc14A, Ndc80/Hec1 and Aurora kinase B. The results show that actively cycling keratinocytes initiate terminal differentiation, arrest in mitosis, continue DNA replication in a special G2/M state, and become polyploid by mitotic slippage. They unambiguously demonstrate that cell cycle progression coexists with terminal differentiation, thus explaining how differentiating cells increase in size. Epidermal differentiating cells arrest in mitosis and a genotoxic-induced mitosis block rapidly pushes epidermal basal cells into differentiation and polyploidy. These observations unravel a novel mitosis-differentiation link that provides new insight into skin homeostasis and cancer. It might constitute a self-defence mechanism against oncogenic alterations such as Myc deregulation.
authors.affiliation: Laboratoire de Dermatologie Moléculaire, UPRES EA3754, Institut Universitaire de Recherche Clinique, UMI/INSERM, Montpellier, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Zanet
authors.forename: Ana
authors.initials: A
authors.lastname: Freije
authors.forename: María
authors.initials: M
authors.lastname: Ruiz
authors.forename: Vincent
authors.initials: V
authors.lastname: Coulon
authors.forename: J Ramón
authors.initials: JR
authors.lastname: Sanz
authors.forename: Jean
authors.initials: J
authors.lastname: Chiesa
authors.forename: Alberto
authors.initials: A
authors.lastname: Gandarillas
mesh_terms: D000818:Animals; D001706:Biopsy; D002453:Cell Cycle; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D004261:DNA Replication; D000078404:Epidermal Cells; D006706:Homeostasis; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D008938:Mitosis; D009693:Nucleic Acid Hybridization; D010766:Phosphorylation; D011123:Polyploidy; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012867:Skin / Q000473:pathology
chemical_list: D016271:Proto-Oncogene Proteins c-myc