Retinoic acid inhibits transformation by preventing phosphatidylinositol 3-kinase dependent activation of the c-fos promoter

Retinoic acid inhibits transformation of cells by polyoma virus middle T on coprotein. Inhibition of transformation results from a retinoic acid-depend ent failure of cells to fully express the c-fos proto-oncogene. Retinoic ac id prevents transactivation of the c-fos promoter by disrupting signaling b etween tyrosine kinases at the plasma membrane and trans-acting factors at the c-fos promoter. We used complementary genetic, biochemical and molecula r approaches to demonstrate that: (1) phosphatidylinositol 3-kinase signali ng is the principle mechanism of polyoma virus middle T oncoprotein activat ion of c-fos expression; (2) middle T/phosphatidylinositol 3-kinase transac tivation of the c-fos promoter and transformation of cells requires activat ion of both the small GTP-binding protein Rac and Jun N-terminal kinase; (3 ) retinoic acid inhibits activation of Jun N- terminal kinase, thereby prev enting c-fos transactivation and transformation; and (4) middle T activatio n of c-fos transcription requires both the serum response element and the p romoter proximal cyclic AMP response element. These studies identify a nove l target through which retinoids prevent oncogenic transformation.