Reversion of Ras transformed cells by Ets transdominant mutants

Considerable progress has been made in elucidating the components of the Ras signalling pathway, from both biochemical and genetic investigations. However little is known about the nuclear targets of the pathway, and in particular those that mediate the long-term changes in gene expression resulting from Ras transformation. Ets family members may be involved in these processes since Ras stimulates transcription through ets-DNA binding sites. We show that a mutated Ets protein, delta PU.1, inhibits Ras activation of transcription. Stable expression of delta PU.1 in Ras transformed NIH3T3 fibroblasts reverts the transformed phenotype by many characteristics, including morphology, anchorage independent growth, saturation density, growth in low serum, tumour formation in nude mice and to some extent sensitivity to apoptotic cell death. Similar trans-dominant mutants of c-Ets-1 and c-Ets-2, the most divergent members of the Ets-family to PU.1, also revert Ras transformed cells, as indicated by morphology, anchorage-independent growth, saturation density and doubling time in low serum. Reversion may result from a shared property of the mutants, such as binding to ets motifs in promoters. These results provide evidence for an important role for Ets proteins in Ras transformation.