The avian sarcoma virus ASV 16 contains a new oncogene, p3k, that is homologous to the gene encoding the catalytic subunit of PI 3-kinase. ASV 16 induces oncogenic transformation in chicken embryo fibroblast cultures and hemangiosarcomas in the animal. The work proposed in this application uses the retroviral vector RCAS to express and replicate various mutants of p3k and its targets. It will define the structural and functional consequences of the mutations that activate the oncogenic potential in viral p3k. It will also mark and characterize downstream targets of the viral P3k protein, tracing the signal via the cytoplasmic serine-threonine kinase Akt to genes that are differentially regulated and that determine the neoplastic phenotype of the p3k-transformed cells. A long range goal is to show that differential expression of key targets accounts for the tumorigenic properties of the transformed cell. Angiogenesis is a critical factor in the development of p3k-induced hemangiosarcomas. It will be analyzed in vivo and in vitro. These experiments will seek to elucidate the mechanisms of p3k-induced angiogenesis, deciding between autocrine and paracrine stimulation and identifying angiogenic factors.
| Athuluri-Divakar, Sai Krishna; Vasquez-Del Carpio, Rodrigo; Dutta, Kaushik et al. (2016) A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling. Cell 165:643-55 |
| Hart, Jonathan R; Zhang, Yaoyang; Liao, Lujian et al. (2015) The butterfly effect in cancer: a single base mutation can remodel the cell. Proc Natl Acad Sci U S A 112:1131-6 |
| Hart, Jonathan R; Roberts, Thomas C; Weinberg, Marc S et al. (2014) MYC regulates the non-coding transcriptome. Oncotarget 5:12543-54 |
| Raffeiner, Philipp; Röck, Ruth; Schraffl, Andrea et al. (2014) In vivo quantification and perturbation of Myc-Max interactions and the impact on oncogenic potential. Oncotarget 5:8869-78 |
| Hart, Jonathan R; Garner, Amanda L; Yu, Jing et al. (2014) Inhibitor of MYC identified in a Kröhnke pyridine library. Proc Natl Acad Sci U S A 111:12556-61 |
| Valeri, Nicola; Braconi, Chiara; Gasparini, Pierluigi et al. (2014) MicroRNA-135b promotes cancer progression by acting as a downstream effector of oncogenic pathways in colon cancer. Cancer Cell 25:469-83 |
| Ito, Yoshihiro; Hart, Jonathan R; Ueno, Lynn et al. (2014) Oncogenic activity of the regulatory subunit p85? of phosphatidylinositol 3-kinase (PI3K). Proc Natl Acad Sci U S A 111:16826-9 |
| Grabinski, Nicole; Ewald, Florian (2014) Ibrutinib (ImbruvicaTM) potently inhibits ErbB receptor phosphorylation and cell viability of ErbB2-positive breast cancer cells. Invest New Drugs 32:1096-104 |
| Vogt, Peter K (2012) Retroviral oncogenes: a historical primer. Nat Rev Cancer 12:639-48 |
| Kolesnichenko, Marina; Hong, Lixin; Liao, Rong et al. (2012) Attenuation of TORC1 signaling delays replicative and oncogenic RAS-induced senescence. Cell Cycle 11:2391-401 |
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