Eor-1 and eor-2, two genes that promote Ras and Wnt signaling in Caenorhabditis elegans

The Ras signaling pathway has been studied with great interest because of its role in normal animal development as well as its role in human cancer. Activation of core Ras pathway components, Ras-Raf-MEK-ERK, culminates in the activation and inhibition of nuclear components including transcriptional activators and repressors. Although core Ras pathway components have been identified, much less is known about the transcriptional regulators that influence Ras-mediated processes. The Ras pathway is conserved from worms to humans; therefore, we can learn a great deal about Ras signaling through genetic studies in model organisms such as C. elegans. To identify additional components of the Ras pathway, our lab conducted a genetic screen to isolate mutations that affect Ras-mediated processes in C. elegans. My thesis work has focused on two genes that were identified in this screen, eor-1 and eor-2. We show that eor-1 and eor-2 promote Ras-mediated processes including vulval, excretory duct, and P12 cell fate specifications. eor-1 and eor-2 influence Ras signaling at a step downstream or in parallel to mpk-1 ERK where other transcriptional regulators function. eor-1 and eor-2 cooperate with known transcriptional regulators that function at this step. eor-1 encodes a nuclear BTB/zinc-finger protein similar to human promyelocytic leukemia zinc finger protein (PLZF), which appears to function as a transcriptional repressor and has been implicated in acute promyelocytic leukemia (APL). eor-2 encodes a novel nuclear protein that appears to function closely with eor-1. Together, our data suggest that eor-1 and eor-2 may promote Ras signaling at the level of transcriptional regulation. We also show that eor-1 and eor-2 act downstream or in parallel to the Wnt signaling pathway, which also has roles in normal development and cancer. We hypothesize that eor-1 and eor-2 function at a convergence of the Ras and Wnt pathways where Hox genes also appear to function. We show that Hox expression is altered in the absence of eor-1, suggesting that eor-1 and perhaps eor-2 influence Ras and Wnt signaling through the regulation of Hox genes. Our future studies will help elucidate mechanisms by which Ras and Wnt pathways cooperate to regulate cellular output