The Pl3-kinase signaling pathway is upregulated in numerous cancers. Hot spot mutations in the catalytic subunit of PI3-kinase, p110 alpha, occur in approximately 30% of several types of solid tumors. The goal of this proposal is to understand the molecular mechanism underlying the oncogenic transformation induced by cancer specific mutant p110 alpha and provide insight into the design of mutant specific inhibitors as anti- cancer drugs. The experiments proposed in this application will make extensive use of retroviral constructs to analyze oncogenic transformation induced by p110 alpha mutants. p85 and Ras have been shown to regulate the kinase activity of p110 alpha. I will examine if oncogenic p110 alpha losses the inhibitory regulation by p85 via in vitro kinase assays and in vivo cell transformation assays. I will determine if the oncogenicity of p110 alpha depends on Ras binding and causes constitutive activation of Ras using biochemical analysis, cell transformation assay, and RNAi. I have identified a new p110 alpha-binding partner, elF3i/Trip1. Here, I will first test the importance of elF3i/Trip1 in PI3-kinase transformation by knocking down elF3i/Trip1, and then investigate the possible impact of oncogenic p110 alpha on translation initiation mediated by elF3i and transcriptional regulation mediated by TGF beta/Tripl pathways. [unreadable] [unreadable] [unreadable]
NIH ExPorter
NIH ExPorter