Oncogenic regulation and function of keratins 8 and 18

Abstract

Keratin 8 (K8) and keratin 18 (K18) are the most common and characteristic members of the large intermediate filament gene family expressed in 'simple' or single layer epithelial tissues of the body. Their persistent expression in tumor cells derived from these epithelia has led to the wide spread use of keratin monoclonal antibodies as aids in the detection and identification of carcinomas. Oncogenes which activate ras signal transduction pathways stimulate expression of the K18 gene through transcription factors including members of the AP-1 (jun and fos) and ETS families. The persistent expression of K8 and K18 may reflect the integrated transcriptional activation of such transcription factors and, in the cases of ectopic expression, an escape from the suppressive epigenetic mechanisms of DNA methylation and chromatin condensation. Comparison of the mechanisms of transcriptional control of K18 expression with expression patterns documented in both normal and pathological conditions leads to the proposal that persistent K8 and K18 expression is a reflection of the action of multiple different oncogenes converging on the nucleus through a limited number of transcription factors to then influence the expression of a large number of genes including these keratins. Furthermore, correlation of various tumor cell characteristics including invasive behavior and drug sensitivity with K8 and K18 expression has stimulated consideration of the possible functions of these proteins in both normal development and in tumorigenesis. Recent developments in the analysis of the functions of these intermediate filament proteins provide new insights into diverse functions influenced by K8 and K18.

Gene expression and amplification in breast carcinoma cells with intrinsic and acquired doxorubicin resistance

“…Overexpression of keratinin 14 has been noted in a recent array study of breast cancer (Martin et al, 2000) and was associated with tumor size. Regulation of keratins 8 and 18 through the ras signalling pathway has been reported (Oshima et al, 1996). In this study the greatest increase in expression of both keratins 8 and 18 was in the ESRa positive cell lines MCF7WT and ZR75-1 relative to the HBL100 cell line, and in these comparisons there was a signi®cant increase in Nras expression in the MCF7WT and ZR75-1 cells (data not shown, available as supplementary data).…”

Epithelium-specific ets transcription factor 2 upregulates cytokeratin 18 expression in pulmonary epithelial cells through an interaction with cytokeratin 18 intron 1

“…K18 gene expression is actively regulated by the first intron of the gene [32,33,35]. There are multiple EBSs within the first intron, some of which have been shown to be involved in gene regulation [31][32][33], and Ese-2 is one Ets factor for which these sites may be targets.…”

Ectopic Expression of PA2.26 Antigen in Epidermal Keratinocytes Leads to Destabilization of Adherens Junctions and Malignant Progression

“…Thus, PA2.26-induced reorganization of the actin cytoskeleton could lead to up-regulation of keratin K8 and vimentin and repression of basal keratin K14 expression. Although the molecular mechanism for these regulatory changes has not been identified, it is likely to involve AP-1 and ETS transcription factors, which have been implicated in the anomalous expression of simple epithelial keratins in carcinomas and of vimentin in migrating epithelial cells (Gilles et al, 1999;Oshima et al, 1996).…”