Oncogene activation of human keratin 18 transcription via the Ras signal transduction pathway.

Keratin 8 (K8) and keratin 18 (K18) are intermediate filament proteins normally expressed in simple epithelial tissues and persistently expressed in a wide variety of carcinomas. Ectopic expression of K8 and K18 occurs in some epidermal and murine skin carcinomas induced by chemical carcinogenesis or oncogenic ras expression. We show here that K18 is a direct target of the Ras signal transduction pathway, by demonstrating that activated Ha-Ras, as well as activated Src, Lck, or Raf, stimulates the transcription of K18. This activation is mediated by an enhancer element containing essential and closely spaced Ets and AP-1 transcription factor binding sites. Oncogene activation of K18 transcription provides a molecular explanation for the persistent and sometimes unexpected expression of K18 in such a wide variety of tumors.