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.
The Ect2 protein has been shown to be overexpressed in human tumors and to play a role in the growth of cancer cells. However, little is known about the mechanisms by which Ect2 functions in tumors. Our preliminary studies indicate that Ect2 is required for the growth of the cells responsible for the initiation and maintenance of lung tumors and that localization of Ect2 within the nucleus of cancer cells is important for their malignant behavior. This project will determine the role that Ect2 plays in initiating lung tumors and the function(s) of Ect2 within the nucleus of lung cancer cells that may be exploited for the development of novel therapeutics for lung cancer, the number one cause of cancer death in the United States.
| Fields, Alan P; Ali, Syed A; Justilien, Verline et al. (2017) Targeting oncogenic protein kinase C? for treatment of mutant KRAS LADC. Small GTPases 8:58-64 |
| Wang, Y; Justilien, V; Brennan, K I et al. (2017) PKC? regulates nuclear YAP1 localization and ovarian cancer tumorigenesis. Oncogene 36:534-545 |
| Justilien, Verline; Ali, Syed A; Jamieson, Lee et al. (2017) Ect2-Dependent rRNA Synthesis Is Required for KRAS-TRP53-Driven Lung Adenocarcinoma. Cancer Cell 31:256-269 |
