Regulation of C-X-C chemokine gene expression by keratin 17 and hnRNP K in skin tumor keratinocytes

Abstract

Interaction between K17 and hnRNP K regulates CXCR3 signaling in an RSK-dependent fashion to promote epithelial tumor cell growth and invasion.

Loss of Keratin 17 induces tissue-specific cytokine polarization and cellular differentiation in HPV16-driven cervical tumorigenesis in vivo

“…16–23 In mouse models for SCC or BCC (basal cell carcinoma), the genetic loss of Krt17 attenuates tumorigenesis, in part through a dampening of a tumor-promoting cytokine profile that results in reduced recruitment of inflammatory and effector immune cell to sites of tumor formation. 23 A similar phenomenon occurs in tumor cell models in culture, 22–24 adding to the evidence that K17 contributes to regulating cytokine expression in a skin keratinocyte-autonomous fashion. From this progress, one infers that K17’s status must be upgraded from biomarker to effector in a variety of chronic inflammatory epithelial disorders.…”

Types I and II Keratin Intermediate Filaments

“…As another example, K17 plays a significant role in the expression of several inflammatory and immune-response genes that are part of a growth-promoting signature in various types of cancers. This involves the interaction of K17 with the heterogeneous ribonucleoprotein hnRNP K and autoimmune regulator (AIRE), a transcriptional regulator functioning in the nucleus (Chung et al 2015; Hobbs et al 2015). Although much remains to be discovered and understood about the role of these and other keratins in epithelial growth control, it is already clear that this phenomenon is poised to impact several chronic inflammatory disorders, ranging from liver and bowel disorders to several types of skin conditions.…”

Skin Keratins

“…Both detergents can maintain some protein–protein interactions and solubilize a fraction of keratins. Our laboratory has adapted the Lowthert protocol over time and currently uses 1% Triton X-100 containing 2% Empigen BB for antigen extraction towards IP assays (Chung et al, 2015) (see Fig. 4C for an example of K16 coimmunoprecipitation (Co-IP) results).…”

“…So when immunoprecipitating K17 from keratinocytes in culture other keratins such as K5, K6, and K14 will coimmunoprecipitate. The immunoglobulin G heavy chain (~55 kDa) falls in within the size range of most keratins (40–60 kDa), so to avoid interference from the heavy chain we use TrueBlot ® Anti-Rabbit Ig IP Beads to immunoprecipitate keratins using rabbit antibodies and TrueBlot ® Anti-Rabbit-HRP secondary antibody to detect proteins by western blotting (Chung et al, 2015). Alternatively, cross-linking antibody to the beads can circumvent this problem, because the antibody will remain attached to the beads during protein elution (Bernot, Coulombe, & Wong, 2004).…”

“…Additionally, keratin filaments act as platforms that modulate cellular and molecular events including migration (Rotty & Coulombe, 2012), innate immunity (Lessard et al, 2013; Roth et al, 2012; Tam, Mun, Evans, & Fleiszig, 2012), hair cycling (Tong & Coulombe, 2006), and tumor progression (Chung et al, 2015; Depianto, Kerns, Dlugosz, & Coulombe, 2010; Hobbs et al, 2015) as well as other fundamental cell processes including growth and programed cell death (e.g., apoptosis) (Gilbert, Loranger, Daigle, & Marceau, 2001; Inada et al, 2001; Kim & Coulombe, 2007; Kim, Wong, & Coulombe, 2006; Ku & Omary, 2006). Mutations that possibly disrupt both structural and nonstructural roles of select keratins (K6, K16, or K17) underlie the cutaneous disorders pachyonychia congenita and steatocystoma multiplex (K17) (McLean & Moore, 2011, McLean et al, 1995).…”