PI 3-kinase and Akt, a lipid and the protein kinase, belong to the same signaling chain. The corresponding genes, inserted into retroviral genomes, show strong oncogenic potential. PI 3-kinase and Akt also play important roles in human cancer. They acquire increased function by amplification or overexpression or by loss of the negative regulator of PI 3-kinase, PTEN. The experiments proposed in this application make extensive use of retroviral constructs to analyze oncogenic transformation induced by the oncoproteins P3k (homolog of the catalytic subunit of PI 3-kinase) and Akt. Work carried out during the past project period has shown that oncogenic transformation induced by these two oncoproteins involves the regulation of transcription and of translation. The components of transcriptional control that participate in the transformation process include the transcriptional regulators NFkB and FKHR, studied in the previous grant period and PLZF, an antagonist of Akt. The proposed studies on PLZF will define the mechanism of interference between PLZF and Akt and identify differentially transcribed genes important in Akt-induced transformation. The translational controls essential for P3k and Akt-induced transformation are governed by the TOR kinase and are highly sensitive to rapamycin. Studies on TOR signaling will concentrate on the TOR signaling motif TOS and the components of the translation initiation complex. An important part of the proposed work will analyze a novel target of Akt, the YB-1 protein. YB-1 binds to RNA as well as DNA and is involved in translational and transcriptional controls. Preliminary data suggest that the interference of YB-1 with Akt-induced transformation depends on binding to mRNA. Future work with YB-1 will use mutant analysis to elucidate the mechanism by which this protein affects Akt signaling and transformation. The studies on TOR and YB-1 are complementary. They illuminate a critical phase in Akt-induced transformation from different angles.
| 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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