title: Keratin-dependent regulation of Aire and gene expression in skin tumor keratinocytes.
abstract: Expression of the intermediate filament protein keratin 17 (K17) is robustly upregulated in inflammatory skin diseases and in many tumors originating in stratified and pseudostratified epithelia. We report that autoimmune regulator (Aire), a transcriptional regulator, is inducibly expressed in human and mouse tumor keratinocytes in a K17-dependent manner and is required for timely onset of Gli2-induced skin tumorigenesis in mice. The induction of Aire mRNA in keratinocytes depends on a functional interaction between K17 and the heterogeneous nuclear ribonucleoprotein hnRNP K. Further, K17 colocalizes with Aire protein in the nucleus of tumor-prone keratinocytes, and each factor is bound to a specific promoter region featuring an NF-κB consensus sequence in a relevant subset of K17- and Aire-dependent proinflammatory genes. These findings provide radically new insight into keratin intermediate filament and Aire function, along with a molecular basis for the K17-dependent amplification of inflammatory and immune responses in diseased epithelia.
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Hobbs
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Daryle J
authors.initials: DJ
authors.lastname: DePianto
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Justin T
authors.initials: JT
authors.lastname: Jacob
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Minerva C
authors.initials: MC
authors.lastname: Han
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Byung-Min
authors.initials: BM
authors.lastname: Chung
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Adriana S
authors.initials: AS
authors.lastname: Batazzi
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Poll
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Jingnan
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: SuFey
authors.initials: S
authors.lastname: Ong
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Zheng
authors.affiliation: 1] Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. [2] Department of Dermatology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Janis M
authors.initials: JM
authors.lastname: Taube
authors.affiliation: 1] Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA. [2] Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Čiháková
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA. [2] Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. [3] Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Fengyi
authors.initials: F
authors.lastname: Wan
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA. [2] Department of Dermatology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. [3] Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. [4] Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. [5] Department of Biological Chemistry, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Pierre A
authors.initials: PA
authors.lastname: Coulombe
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D017403:In Situ Hybridization; D053537:Keratin-17 / Q000235:genetics* / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000096927:AIRE Protein
chemical_list: D053537:Keratin-17; D014157:Transcription Factors; D000096927:AIRE Protein