Accumulating evidence from both cell and animal-based model systems indicates the Ras-like small GTP-binding proteins RalA and RalB are core components of a regulatory framework supporting tumorigenic transformation. Recently we have established discrete but interlocking contributions of these highly related G-proteins to the regulation of both cancer and cell proliferation and survival. Specifically, chronic activation of RalA is required to maintain anchorage-independent proliferation, while RalB is required to deflect cell-death checkpoint activation. This proposal is directed at defining the composition, organization, and function of cell regulatory networks engaged by Ral family G-proteins. Our focus is on the dominant RalA and RalB effector pathways that directly participate in oncogenic transformation.
Our specific aims are 1) identification of the effector pathway(s) mediating RalA support of anchorage-independent proliferation, 2) defining the mechanistic contribution of RalB signaling to cancer cell survival, and 3) evaluating the consequences of perturbations in RalA/RalB signaling networks to tumor initiation and/or progression in xenograft and organotypic model systems.
|Torres, Michael J; Pandita, Raj K; Kulak, Ozlem et al. (2015) Role of the Exocyst Complex Component Sec6/8 in Genomic Stability. Mol Cell Biol 35:3633-45|
|Shields, Benjamin B; Pecot, Chad V; Gao, Hua et al. (2015) A genome-scale screen reveals context-dependent ovarian cancer sensitivity to miRNA overexpression. Mol Syst Biol 11:842|
|Kim, Hyun Seok; Mendiratta, Saurabh; Kim, Jiyeon et al. (2013) Systematic identification of molecular subtype-selective vulnerabilities in non-small-cell lung cancer. Cell 155:552-66|
|Cooper, Jonathan M; Bodemann, Brian O; White, Michael A (2013) The RalGEF/Ral pathway: evaluating an intervention opportunity for Ras cancers. Enzymes 34 Pt. B:137-56|
|Kim, Hyun Seok; Minna, John D; White, Michael A (2013) GWAS meets TCGA to illuminate mechanisms of cancer predisposition. Cell 152:387-9|
|Potts, Malia B; Kim, Hyun Seok; Fisher, Kurt W et al. (2013) Using functional signature ontology (FUSION) to identify mechanisms of action for natural products. Sci Signal 6:ra90|
|Ward, Samuel E; Kim, Hyun Seok; Komurov, Kakajan et al. (2012) Host modulators of H1N1 cytopathogenicity. PLoS One 7:e39284|
|Herman, Melina; Ciancanelli, Michael; Ou, Yi-Hung et al. (2012) Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood. J Exp Med 209:1567-82|
|Wang, Richard C; Wei, Yongjie; An, Zhenyi et al. (2012) Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science 338:956-9|
|Bodemann, Brian O; Orvedahl, Anthony; Cheng, Tzuling et al. (2011) RalB and the exocyst mediate the cellular starvation response by direct activation of autophagosome assembly. Cell 144:253-67|
Showing the most recent 10 out of 13 publications