Loss of epidermal AP1 transcription factor function reduces filaggrin level, alters chemokine expression and produces an ichthyosis-related phenotype
JournalCell death & disease
MetadataShow full item record
AbstractAP1 transcription factors are important controllers of epidermal differentiation. Multiple family members are expressed in the epidermis in a differentiation-dependent manner, where they function to regulate gene expression. To study the role of AP1 factor signaling, TAM67 (dominant-negative c-jun) was inducibly expressed in the suprabasal epidermis. The TAM67-positive epidermis displays keratinocyte hyperproliferation, hyperkeratosis and parakeratosis, delayed differentiation, extensive subdermal vasodilation, nuclear loricrin localization, tail and digit pseudoainhum and reduced filaggrin level. These changes are associated with increased levels of IFN?, CCL3, CCL5, CXCL9, CXCL10, and CXCL11 (Th1-associated chemokines), and CCL1, CCL2, CCL5 and CCL11 (Th2-associated chemokines) in the epidermis and serum. S100A8 and S100A9 protein levels are also markedly elevated. These changes in epidermal chemokine level are associated with increased levels of the corresponding chemokine mRNA. The largest increases were observed for CXCL9, CXCL10, CXCL11, and S100A8 and S100A9. To assess the role of CXCL9, CXCL10, CXCL11, which bind to CXCR3, on phenotype development, we expressed TAM67 in CXCR3 knockout mice. Using a similar strategy, we examine the role of S100A8 and S100A9. Surprisingly, loss of CXCR3 or S100A8/A9 did not attenuate phenotype development. These studies suggest that interfering with epidermal AP1 factor signaling initiates a loss of barrier function leading to enhanced epidermal chemokine production, but that CXCR3 and S100A8/A9 do not mediate the phenotypic response.
Intermediate Filament Proteins--genetics
Proto-Oncogene Proteins c-jun--genetics
Transcription Factor AP-1--genetics
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85043361409&doi=10.1038%2fcddis.2017.238&partnerID=40&md5=2a2c1174c7f53456d679c46bb0034950; http://hdl.handle.net/10713/11349
- Structural and biochemical changes underlying a keratoderma-like phenotype in mice lacking suprabasal AP1 transcription factor function.
- Authors: Rorke EA, Adhikary G, Young CA, Rice RH, Elias PM, Crumrine D, Meyer J, Blumenberg M, Eckert RL
- Issue date: 2015 Feb 19
- Embryonic AP1 Transcription Factor Deficiency Causes a Collodion Baby-Like Phenotype.
- Authors: Young CA, Eckert RL, Adhikary G, Crumrine D, Elias PM, Blumenberg M, Rorke EA
- Issue date: 2017 Sep
- Suppression of AP1 transcription factor function in keratinocyte suppresses differentiation.
- Authors: Han B, Rorke EA, Adhikary G, Chew YC, Xu W, Eckert RL
- Issue date: 2012
- AP1 factor inactivation in the suprabasal epidermis causes increased epidermal hyperproliferation and hyperkeratosis but reduced carcinogen-dependent tumor formation.
- Authors: Rorke EA, Adhikary G, Jans R, Crish JF, Eckert RL
- Issue date: 2010 Nov 4
- Suppressing AP1 factor signaling in the suprabasal epidermis produces a keratoderma phenotype.
- Authors: Rorke EA, Adhikary G, Young CA, Roop DR, Eckert RL
- Issue date: 2015 Jan