2026-04-29T07:22:13Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/102632024-11-29T22:49:53Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Wurm, Stefanie
author
Zhang, Jisheng
author
Guinea-Viniegra, Juan
author
García, Fernando
author
Muñoz, Javier
author
Bakiri, Latifa
author
Ezhkova, Elena
author
Wagner, Erwin F
author
Munoz, Javier
author
Wagner, Erwin F.
funder
Fundación BBVA
funder
Unión Europea. Comisión Europea. European Research Council (ERC)
funder
Ministerio de Economía y Competitividad (España)
funder
United States Department of Health and Human Services
funder
Natural Science Foundation of Shandong Province (China)
2020-06-03T15:05:27Z
2020-06-03T15:05:27Z
2015-01-15
Genes Dev . 2015;29(2):144-56
0890-9369
http://hdl.handle.net/20.500.12105/10263
25547114
10.1101/gad.249748.114
1549-5477
Genes & development
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.
eng
Terminal epidermal differentiation is regulated by the interaction of Fra-2/AP-1 with Ezh2 and ERK1/2.
journal article
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