C/EBPβ's role in determining Ras-induced senescence or transformation

Abstract

Introduction of activated Ras into normal cells leads to senescence, a tumor suppressive mechanism, whereas expression of this oncogene in many immortalized cell lines leads to transformation. Studying the signaling differences in cells that undergo Ras-induced senescence versus Ras transformation may shed light on potential therapeutic targets in the treatment of cancer. C/EBPβ is a transcription factor necessary for both Ras-induced senescence and Ras transformation. Three isoforms of this transcription factor exist due to alternative translation initation at three in frame ATGs. C/EBPβ1 is the isoform responsible for oncogene-induced senescence, and this isoform is degraded by the proteosome during Ras transformation. Phosphorylation of C/EBPβ1 on Thr235 by Cdk2 is necessary, but not sufficient, for degradation of C/EBPβ1. Proteasomal degradation of C/EBPβ1 may represent a mechanism to evade senescence. In contrast, C/EBPβ2 is expressed in breast cancer cells and is involved in proliferation, supporting a role for this isoform in Ras transformation. We propose here that one potential signaling difference in Ras-induced senescence versus Ras transformation is that Ras signals through different C/ EBPβ isoforms (C/EBPβ1 versus C/ EBPβ2) during these processes.