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Genes Dev. 2015 Jan 15;29(2):144-56. doi: 10.1101/gad.249748.114. Epub 2014 Dec 29.

Terminal epidermal differentiation is regulated by the interaction of Fra-2/AP-1 with Ezh2 and ERK1/2.

Author information

1
BBVA Foundation-CNIO Cancer Cell Biology Program, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain;
2
Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province 266500, China;
3
Proteomics Unit, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain;
4
Developmental and Regenerative Biology, Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, New York 10029, USA.
5
BBVA Foundation-CNIO Cancer Cell Biology Program, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain; ewagner@cnio.es.

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.

KEYWORDS:

ERK1/2; Ezh2/PRC2; Fra-2/AP-1; epidermal differentiation complex; nonhistone substrate

PMID:
25547114
PMCID:
PMC4298134
DOI:
10.1101/gad.249748.114
[Indexed for MEDLINE]
Free PMC Article

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