Cancer is a disease in which growth stimulatory pathways are excessively active. Considerable experimental evidence implicates Ras proteins as essential components of growth stimulatory signal transduction pathways and mutated Ras proteins as important contributors to human carcinogenesis. The broad objective of this research project is to define the molecular mechanisms underlying the growth promoting activity of Ras. The combined efforts of many groups, including our own, have led to the realization that the biological effects of Ras are mediated by a network of interconnecting pathways. However, the distinct contribution of these pathways to the mitogenic and oncogenic effects of Ras has remained poorly defined. During the past grant period, we have identified effector pathways that mediate the proliferative and cell survival responses to Ras. The goal of the studies proposed in the current application is to define the mechanisms by which these effector pathways contribute to both normal and deregulated cell growth.
Our specific aims are as follows: 1. To define the mechanisms by which Rac contributes to Ras-induced cell cycle progression. 2. To identify Rac-dependent effector activities that mediate the mitogenic response. 3. To establish the role of Ras-dependent cell survival signals in oncogenic transformation. 4. To identify the signaling activities of Ras involved in pancreatic cancer. Together, the experiments proposed herein should serve the dual purpose of advancing our understanding of growth control in normal cells and providing insights into how the regulation of cell growth is disturbed in cancer cells.
| Grabocka, Elda; Commisso, Cosimo; Bar-Sagi, Dafna (2015) Molecular pathways: targeting the dependence of mutant RAS cancers on the DNA damage response. Clin Cancer Res 21:1243-7 |
| Grabocka, Elda; Pylayeva-Gupta, Yuliya; Jones, Mathew J K et al. (2014) Wild-type H- and N-Ras promote mutant K-Ras-driven tumorigenesis by modulating the DNA damage response. Cancer Cell 25:243-56 |
| Pylayeva-Gupta, Yuliya; Lee, Kyoung Eun; Bar-Sagi, Dafna (2013) Microdissection and culture of murine pancreatic ductal epithelial cells. Methods Mol Biol 980:267-79 |
| Pylayeva-Gupta, Yuliya; Lee, Kyoung Eun; Hajdu, Cristina H et al. (2012) Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 21:836-47 |
| Zheng, Ze-Yi; Xu, Lizhong; Bar-Sagi, Dafna et al. (2012) Escorting Ras. Small GTPases 3:236-9 |
| Jeng, Hao-Hsuan; Taylor, Laura J; Bar-Sagi, Dafna (2012) Sos-mediated cross-activation of wild-type Ras by oncogenic Ras is essential for tumorigenesis. Nat Commun 3:1168 |
| Mallen-St Clair, Jon; Soydaner-Azeloglu, Rengin; Lee, Kyoung Eun et al. (2012) EZH2 couples pancreatic regeneration to neoplastic progression. Genes Dev 26:439-44 |
| Ochi, Atsuo; Nguyen, Andrew H; Bedrosian, Andrea S et al. (2012) MyD88 inhibition amplifies dendritic cell capacity to promote pancreatic carcinogenesis via Th2 cells. J Exp Med 209:1671-87 |
| Pylayeva-Gupta, Yuliya; Grabocka, Elda; Bar-Sagi, Dafna (2011) RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer 11:761-74 |
| Xu, Lizhong; Lubkov, Veronica; Taylor, Laura J et al. (2010) Feedback regulation of Ras signaling by Rabex-5-mediated ubiquitination. Curr Biol 20:1372-7 |
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