ONCOGENIC REGULATION AND FUNCTION OF KERATIN-8 AND KERATIN-18

Keratin 8 (K8) and keratin 18 (K18) are the most common and characteri stic members of the large intermediate filament gene family expressed in 'simple' or single layer epithelial tissues of the body. Their pers istent 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 f os) and ETS families. The persistent expression of K8 and K18 may refl ect the integrated transcriptional activation of such transcription fa ctors and, in the cases of ectopic expression, an escape from the supp ressive epigenetic mechanisms of DNA methylation and chromatin condens ation. Comparison of the mechanisms of transcriptional control of K18 expression with expression patterns documented in both normal and path ological conditions leads to the proposal that persistent K8 and K18 e xpression is a reflection of the action of multiple different oncogene s converging on the nucleus through a limited number of transcription factors to then influence the expression of a large number of genes in cluding 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 fu nctions of these proteins in both normal development and in tumorigene sis. Recent developments in the analysis of the functions of these int ermediate filament proteins provide new insights into diverse function s influenced by Kg and K18.