BIDIRECTIONAL REGULATION OF C-FOS PROMOTER BY AN ONCOGENIC GIP2 MUTANT OF G-ALPHA(12) - A NOVEL IMPLICATION OF RETINOBLASTOMA GENE-PRODUCT

G alpha(i2) is a tissue-specific proto-oncogene product, whose activat ed mutant gip2 induces transformation through less defined downstream pathways, We found that c-fos promoter is a target of gip2 in multiple kinds of cells, Serum response element was shown to be the positive e nhancer element that mediates gip2-induced c-fos expression. We furthe r demonstrated that gip2 stimulates the negative silencer activity of the retinoblastoma (Rb) control element (RCE) and inhibits the c-fos p romoter activity through RCE located in the c-fos promoter region. The effect of gip2 on RCE was shown to be mediated by the Rb gene product (pRb). Furthermore, gip2 augmented underphosphorylated active form of pRb by promoting pRb expression and by affecting the phosphorylation state of pRb. gip2 therefore propagates both positive and negative sig nals to the c-fos promoter through two different elements, and pRb med iates the negative signal of gip2. We conclude that gip2 has bifunctio nal roles in transformation which pRb critically regulates. Given that Rat-1 cells, which gip2 can transform, lack the sensitivity to the gi p2/pRb-mediated negative pathway, this study provides a novel insight into oncogenesis by gip2 and its tissue specificity.