Downregulation of the colon tumour-suppressor homeobox gene Cdx-2 by oncogenic ras

Constitutive activation of the ras proto-oncogene is a frequent and early e vent in colon cancers, but the downstream nuclear targets are not fully und erstood. The Cdx-1 and Cdx-2 homeobox genes play crucial roles in intestina l cell proliferation and differentiation, In addition, Cdx-2 is a colonic t umour-suppressor gene, whereas Cdx-1 has oncogenic potential. Here, we show that constitutive activation of ras alters Cdx-1 and Cdx-2 expression in h uman colonic Caco-2 and HT-29 cells that harbour a normal ras proto-oncogen e. Oncogenic ras downregulates Cdx-2 through activation of the PKC pathway and a decline in activity of the Cdx-2 promoter AP-1 site, This decline res ults from a PKC-dependent decrease in the relative expression of c-Jun, an activator of Cdx-2 transcription, compared to c-Fos, an inhibitor of Cdx-2. Unlike Cdx-2, Cdx-1 is upregulated by oncogenic ras and this effect is med iated by activation of the MEK1 pathway. These results indicate that oncoge nic ras activation has opposite effects on Cdx-1 and Cdx-2 expression throu gh distinct signalling pathways and they provide the first evidence for a f unctional link between ras activation and the downregulation of the Cdx-2 t umour-suppressor gene in colon cancer cells.