Characterization of ATF2 in Rel/NFκB oncogenesis reveals its role in the regulation of Ras signaling.

The v-Rel oncoprotein is the acutely transforming member of the Rel/NFκB family of transcription factors. v-Rel transforms cells through the inappropriate activation and suppression of genes normally regulated by cellular Rel/NFκB family members. We have recently demonstrated that activation of Ha-Ras by v-Rel contributes to transformation. Characterization of AP-1 family members in v-Rel-mediated transformation revealed ectopic expression of ATF2 inhibited transformation by blocking Ha-Ras activity. This lack of Ha-Ras activity prevented downstream activation of the Raf-MEK-ERK pathway, a critical pathway for v-Rel-mediated transformation. Microarray analysis of cells treated with an inhibitor to the ERK pathway revealed a relatively small number of genes that are specifically regulated by ERK activity in cells expressing v-Rel. These studies suggest the main contribution of ERK activity is to temper the expression of genes in v-Rel transformed cells. The mechanism by which ATF2 regulates Ras-Raf-MEK-ERK signaling appears to be a context dependent event. The ectopic expression of ATF2 in cells that are not expressing v-Rel results in the activation of Ha-Ras. However, activation of downstream Raf-MEK-ERK signaling pathway is blocked, likely through the recruitment of inhibitory 14-3-3 proteins to c-Raf. These results suggest a diverse role for ATF2 in the regulation of the Ras-Raf-MEK-ERK pathway.