Abstract IA06: Oncogenic translation programs

Abstract

Abstract New York, NY. I will provide an overview of the lab's contribution to deciphering the role of aberrant mRNA translation in cancer. We initially reported that aberrant eIF4E expression can drive lymphomagenesis in vivo. Next, we noticed that eIF4E's oncogenic activity strictly required phosphorylation at S209 by MNK1/2 kinases. The latter is the basis of ongoing efforts to develop and test MNK kinase inhibitors for cancer applications. More recently, we dissected the molecular basis of the anti-cancer action of eIF4A inhibitors like silvestrol. Using the ribosome footprinting technology developed by the Weissman lab we noticed that eIF4A inhibition acutely and preferentially suppressed a select group of ~200 mRNAs. These are marked by repeated 5' UTR sequences that are predicted to fold into energetically favorable G-quadruplex structures. Notably, many of these eIF4A–dependent transcripts encode oncogenic transcription factors (e.g. MYC and MYB), a number of cell cycle regulators (e.g. CDK6, CCND3), and anti-apoptotic BCL2 family genes. These findings also begin to shed light on the overarching question of how aberrant translation may lead to cancer. We speculate that it is not simply a global increase in protein production but instead the activation of oncogenic translation programs. We will discuss these findings also in light of recent work proposing an additional mechanism of eIF4A action that emphasizes binding to ubiquitous RNA sequence elements over the enzymatic activity of eIF4A. Citation Format: Hans-Guido Wendel. Oncogenic translation programs. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA06.