title: Epidermal hyperplasia induced by Raf-MAPK signaling requires Stat3 activation.
abstract: BACKGROUND
  Raf is one of the downstream effectors of Ras GTPases, and plays a key role in regulating cell proliferation and differentiation through the activation of MAPK. We have previously demonstrated that temporal induction of Raf in the epidermis of K14-Raf:ER transgenic mice results in epidermal hyperplasia resembling squamous cell carcinoma and psoriasis. It has been demonstrated that epidermal Stat3 activation is required for psoriasis development, since keratinocyte-specific Stat3 activation in a mouse model elicits a psoriasis-like phenotype, which is reversed by inhibition of Stat3 signaling.
  
  
  OBJECTIVE
  The aim of this study was whether Stat3 signaling is involved in Raf-MAPK-dependent epidermal hyperplasia.
  
  
  METHODS
  K14-Raf:ER transgenic mice, in which the 4-hydroxytamoxifen (4OHT)-responsive mutant estrogen receptor ligand binding domain-Raf fusion gene is expressed under control of the keratin 14 promoter, were mated with epidermis-specific Stat3 null mice (K5-Cre.Stat3(flox/flox)). K5-Cre.Stat3(flox/flox) mice were used to define the impact of Stat3 deficiency on Raf-induced epidermal hyperplasia.
  
  
  RESULTS
  Over-expression of Raf by 4OHT treatment in K14-Raf:ER;K5-Cre.Stat3(flox/flox) mice greatly attenuated the epidermal hyperplasia and dermal cell infiltrates compared with K14-Raf:ER;K5-Cre.Stat3(flox/WT) mice. Also, up-regulation of psoriasis-associated cytokine profiles, including VEGF, was inhibited in the skin from K14-Raf:ER;K5-Cre.Stat3(flox/flox) mice following 4OHT treatment.
  
  
  CONCLUSIONS
  These results clearly indicate that Raf-MAPK-dependent psoriatic-like epidermal hyperplasia requires Stat3 signaling in keratinocytes.
authors.affiliation: Department of Dermatology, Kochi Medical School, Kochi University, Kohasu, Okocho, Nankoku 783-8505, Japan. Electronic address: tarutani@kochi-u.ac.jp.
authors.forename: Masahito
authors.initials: M
authors.lastname: Tarutani
authors.forename: Kimiko
authors.initials: K
authors.lastname: Nakajima
authors.forename: Mikiro
authors.initials: M
authors.lastname: Takaishi
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ohko
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Sano
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D002454:Cell Differentiation; D004817:Epidermis / Q000473:pathology*; D005786:Gene Expression Regulation; D006801:Humans; D006965:Hyperplasia; D015603:Keratinocytes / Q000166:cytology; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D011565:Psoriasis / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000737:chemistry; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000737:chemistry; D048490:raf Kinases / Q000378:metabolism*
chemical_list: D008024:Ligands; D011960:Receptors, Estrogen; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D013629:Tamoxifen; C016601:afimoxifene; D048490:raf Kinases
keywords: Epidermal hyperplasia; Knockout mice; Raf; Stat3; Transgenic mice