title: Cyclin E drives human keratinocyte growth into differentiation.
abstract: Human epidermis is continuously exposed to environmental mutagenic hazard and is the most frequent target of human cancer. How the epidermis coordinates proliferation with differentiation to maintain homeostasis, even in hyperproliferative conditions, is unclear. For instance, overactivation of the proto-oncogene MYC in keratinocytes stimulates differentiation. Here we explore the cell cycle regulation as proliferating human keratinocytes commit to terminal differentiation upon loss of anchorage or overactivation of MYC. The S-phase of the cell cycle is deregulated as mitotic regulators are inhibited in the onset of differentiation. Experimental inhibition of mitotic kinase cdk1 or kinases of the mitosis spindle checkpoint Aurora B or Polo-like Kinase, triggered keratinocyte terminal differentiation. Furthermore, hyperactivation of the cell cycle by overexpressing the DNA replication regulator Cyclin E induced mitosis failure and differentiation. Inhibition of Cyclin E by shRNAs attenuated the induction of differentiation by MYC. In addition, we present evidence that Cyclin E induces DNA damage and the p53 pathway. The results provide novel clues for the mechanisms committing proliferative keratinocytes to differentiate, with implications for tissue homeostasis maintenance, HPV amplification and tumorigenesis.
authors.affiliation: Cell Cycle, Stem Cell Fate and Cancer Laboratory, Institute for Training and Research of the Fundación Marqués de Valdecilla (IFIMAV-FMDV), Santander, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Freije
authors.forename: L
authors.initials: L
authors.lastname: Ceballos
authors.forename: M
authors.initials: M
authors.lastname: Coisy
authors.forename: L
authors.initials: L
authors.lastname: Barnes
authors.forename: M
authors.initials: M
authors.lastname: Rosa
authors.forename: E
authors.initials: E
authors.lastname: De Diego
authors.forename: J M
authors.initials: JM
authors.lastname: Blanchard
authors.forename: A
authors.initials: A
authors.lastname: Gandarillas
mesh_terms: D064107:Aurora Kinase B; D064127:Aurora Kinases; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004261:DNA Replication; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology; D008938:Mitosis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D016196:S Phase / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000097869:Polo-Like Kinase 1
chemical_list: D064107:Aurora Kinase B; D064127:Aurora Kinases; D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins; D019927:Cyclin E; D017346:Protein Serine-Threonine Kinases; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D000097869:Polo-Like Kinase 1; C000715470:MAS1 protein, human; C576921:AURKB protein, human