The Ras - ERK MAP kinase signaling pathway is critical for establishing cell fates during development. Importantly, mutations that activate the Ras pathway are a prevalent cause of human tumors. A major gap in our current understanding of this pathway is how activation of ERK alters the balance in gene expression to promote cell proliferation. Our long term goal is to understand how the Ras signaling pathway switches the activity of transcription factors so that they promote cell proliferation. We will address this by analyzing transcription factors that respond to Ras-mediated signaling in C. elegans and vertebrates. Understanding how the Ras pathway controls gene expression in development and disease in an important objective of medical research, since the information may lead to new and effective therapies for tumors caused by activated Ras signaling. Our preliminary results have defined exciting new mechanisms for the regulation of the LIN-1 transcription factor by Ras-mediated signaling and support two innovative hypotheses. (1) The LIN-1 transcription factor is post translationally modified by SUMO. Sumoylated LIN-1 represses transcription by interacting with MEP-1, DAS-1 and MAS-1, proteins involved in chromatin remodeling. (2) Activated ERK switches LIN-1 from a sumoylated, transcriptional represser that inhibits cell proliferation to a phosphorylated, transcriptional activator that induces cell proliferation. To test these hypotheses, we propose three specific aims.
Aims 1 and 2: We will use biochemical techniques to define domains and specific residues of MEP-1, MAS-1 and DAS-1 that interact with LIN-1. We will characterize the relevance and specific functions of these interactions in intact animals. These studies will define the mechanisms of SUMO-mediated transcriptional repression and the significance of one DNA binding transcription factor recruiting three different transcriptional repressers.
Aim 3 : We will determine how ERK switches the activity of LIN-1. These studies will elucidate the mechanisms and logic of a switch that is critical for cell fate determination during development. The results of these studies will significantly advance the understanding of how ETS transcription factors are regulated, how SUMO mediates transcriptional repression, and how ERK promotes cell proliferation, and address critical gaps in our current knowledge of these important areas. This switch may also respond to oncogenic signaling pathways, and these studies will provide information that can result in new therapeutic strategies for blocking the proliferation of tumor cells in humans. Lay language: This research will reveal how tumor cells proliferate and suggest new strategies for treating human cancer. ? ? ?
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