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 expr essed in a wide variety of carcinomas. Ectopic expression of K8 and K1 8 occurs in some epidermal and murine skin carcinomas induced by chemi cal carcinogenesis or oncogenic ras expression. We show here that K18 is a direct target of the Ras signal transduction pathway, by demonstr ating that activated Ha-Ras, as well as activated Src, Lck, or Raf, st imulates the transcription of K18. This activation is mediated by an e nhancer element containing essential and closely spaced Ets and AP-1 t ranscription factor binding sites. Oncogene activation of K18 transcri ption provides a molecular explanation for the persistent and sometime s unexpected expression of K18 in such a wide variety of tumors.