P3K, Retroviral Oncogene and Homolog of PI 3-Kinase

Scripps Research Institute, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): 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.