title: Terminal epidermal differentiation is regulated by the interaction of Fra-2/AP-1 with Ezh2 and ERK1/2.
abstract: Altered epidermal differentiation characterizes numerous skin diseases affecting >25% of the human population. Here we identified Fra-2/AP-1 as a key regulator of terminal epidermal differentiation. Epithelial-restricted, ectopic expression of Fra-2 induced expression of epidermal differentiation genes located within the epidermal differentiation complex (EDC). Moreover, in a papilloma-prone background, a reduced tumor burden was observed due to precocious keratinocyte differentiation by Fra-2 expression. Importantly, loss of Fra-2 in suprabasal keratinocytes is sufficient to cause skin barrier defects due to reduced expression of differentiation genes. Mechanistically, Fra-2 binds and transcriptionally regulates EDC gene promoters, which are co-occupied by the transcriptional repressor Ezh2. Fra-2 remains transcriptionally inactive in nondifferentiated keratinocytes, where it was found monomethylated and dimethylated on Lys104 and interacted with Ezh2. Upon keratinocyte differentiation, Fra-2 is C-terminally phosphorylated on Ser320 and Thr322 by ERK1/2, leading to transcriptional activation. Thus, the induction of epidermal differentiation by Fra-2 is controlled by a dual mechanism involving Ezh2-dependent methylation and activation by ERK1/2-dependent phosphorylation.
authors.affiliation: BBVA Foundation-CNIO Cancer Cell Biology Program, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain;
authors.forename: Stefanie
authors.initials: S
authors.lastname: Wurm
authors.affiliation: Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province 266500, China;
authors.forename: Jisheng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: BBVA Foundation-CNIO Cancer Cell Biology Program, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain;
authors.forename: Juan
authors.initials: J
authors.lastname: Guinea-Viniegra
authors.affiliation: Proteomics Unit, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain;
authors.forename: Fernando
authors.initials: F
authors.lastname: García
authors.affiliation: Proteomics Unit, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain;
authors.forename: Javier
authors.initials: J
authors.lastname: Muñoz
authors.affiliation: BBVA Foundation-CNIO Cancer Cell Biology Program, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain;
authors.forename: Latifa
authors.initials: L
authors.lastname: Bakiri
authors.affiliation: Developmental and Regenerative Biology, Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Ezhkova
authors.affiliation: BBVA Foundation-CNIO Cancer Cell Biology Program, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain; ewagner@cnio.es.
authors.forename: Erwin F
authors.initials: EF
authors.lastname: Wagner
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D000071221:Enhancer of Zeste Homolog 2 Protein; D051921:Fos-Related Antigen-2 / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D015603:Keratinocytes / Q000166:cytology*; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D010766:Phosphorylation; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*
chemical_list: D051921:Fos-Related Antigen-2; C497873:Fosl2 protein, mouse; D018808:Transcription Factor AP-1; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2; D019950:Mitogen-Activated Protein Kinase 1; D008239:Lysine
keywords: ERK1/2; Ezh2/PRC2; Fra-2/AP-1; epidermal differentiation complex; nonhistone substrate