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 epithelia1-3. We report that Autoimmune regulator (Aire), a transcriptional regulator, is inducibly expressed in human and mouse tumor keratinocytes in a K17-dependent manner and required for a timely onset of Gli2-induced skin tumorigenesis in mice. Induction of Aire mRNA in keratinocytes depends upon a functional interaction between K17 and the heterogeneous nuclear ribonucleoprotein hnRNP K4. Further, K17 colocalizes with Aire protein in the nucleus of tumor-prone keratinocytes, and each are bound to a specific promoter region featuring a NF-κB consensus sequence in a relevant subset of K17- and Aire-dependent pro-inflammatory 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.

Expression and prognostic significance of the autoimmune regulator gene in breast cancer cells

“…16 AIRE-mediated expression of pro-inflammatory transcripts in skin tumors strictly depends on KRT17 and hnRNP K expression. KRT17 and hnRNP K expression did not differ significantly between AIRE-positive and -negative breast tumors neither in the TCGA nor the NKI-295 dataset (data not shown).…”

“…13 Very recently, AIRE expression was reported in human and mouse keratinocytes and in tumors originating in stratified and pseudostratified epithelia, as head and neck squamous carcinomas. 16,17 Thus, the shared feature of promiscuous expression of some genes by mTECs and cancer cells 18,19 raises the possibility that analogous mechanisms of transcriptional regulation operate in both cell types and that AIRE, as part of or a consequence of such mechanisms, is ectopically activated in some solid human tumors.…”

Oxidative stress and dysfunctional NRF2 underlie pachyonychia congenita phenotypes

“…After DNAse treatment (RNAse free DNase kit: QIAGEN), 1 μg of total RNA from each sample was reverse transcribed (iScript cDNA synthesis kit; BioRad). Quantitative RT-PCR was performed as described (49). The target-specific oligonucleotide primer sets used are listed in Supplemental Table 2.…”

“…For histological analyses, paw tissue samples were submerged in OCT (Sakura Finetek), flash-frozen in liquid nitrogen, and stored at -20°C upon sectioning. Sections of 8 μm were cut in a specific and consistent orientation relative to paw morphology and stained with either H&E for routine histopathology or incubated with primary antibodies and Alexa Fluor-conjugated secondary antibodies for indirect immunofluorescence (49).…”

Selective regulation of Notch ligands during angiogenesis is mediated by vimentin

“…Whereas IFs provide cells with mechanical stability, there is mounting evidence indicating that IFs are involved in a range of metabolic, signaling, and regulatory processes that are unrelated to mechanical functions (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). The vimentin IF has been shown to act as a scaffold for signaling proteins that regulate epithelial mesenchymal transition (EMT), cancer cell invasion, wound healing and tissue repair, tissue aging, as well as inflammatory signaling (3,4,(6)(7)(8)10).…”