? DESCRIPTION (provided by applicant): Epithelial cell transforming sequence 2 (Ect2) has been identified as an oncogene in human tumors. Ect2 is sufficient to drive transformation in fibroblasts, is overexpressed in a variety of tumors and is required for transformed growth of tumor cells. However, the specific mechanism(s) by which Ect2 exerts its oncogenic activity in tumors are currently unknown. Our preliminary studies indicate that: 1) Ect2 GEF activity and nuclear localization are required for transformation, 2) Ect2 co-localizes with the nucleolar protein Upstream Binding Factor 1 (UBF1) and regulates ribosomal RNA (rRNA) synthesis, and 3) genetic loss of Ect2 inhibits Kras/p53-mediated lung tumorigenesis in vivo and growth of lung tumor initiating cells (TICs) ex vivo. Thus, we hypothesize that: 1) Ect2-mediated rRNA transcription is important for lung adenocarcinoma (LADC) transformation and 2) Ect2 drives Kras/p53-mediated LADC formation by maintaining a lung TIC phenotype in vivo. Two specific aims are proposed to test these hypotheses. In Aim 1 we will determine the role of Ect2 regulation of rRNA transcription in LADC transformation and in Aim 2 we will determine the role of Ect2 in the tumorigenicity of LADC TICs in vivo. Completion of these aims will provide insight into the role of Ect2 in the tumorigenic behavior of TICs, enhance our understanding of the initiating events in K-ras-mediated lung tumorigenesis and how a key step in ribosome biosynthesis, rRNA synthesis, may be regulated in tumor cells to promote the transformed phenotype.
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