RAS ACTIVATION OF GENES - MOB-1 AS A MODEL

The ras oncogenes function by indirectly controlling expression of a s ubset of Set-undefined genes that are crucial for cell growth and diff erentiation. In a differential display strategy, numerous genes were i dentified on the basis of their differential expression in rat embryo fibroblasts transformed by the cooperation of mutant Ha-ras and p53 ge nes. We demonstrate here that one such gene, designated mob-1, is a do wnstream target of the Ras signaling pathway. The 417-bp mob-1 promote r, which contains dual NF-kappa B and AP-1 binding sites, confers the pas inducibility. Oncogenic pas as well as serum growth factors that a ctivate endogenous Ras can induce mob-1 expression, but with a fundame ntal difference in that the oncogenic induction is constitutive wherea s the serum induction is transient. mob-1 encodes a small secretory pr otein with a high degree of homology to LP-10, a member of a proinflam matory cytokine family. These findings link chronic inflammatory respo nse to constitutive ras activation and tumorigenesis. Mob-1 may serve as a secreted marker for oncogenic Ha-ras mutations.