Abstract B13: EGF/Ras/Erk signaling controls growth and proliferation through regulation of tRNA synthesis

Abstract

Abstract Ras signaling promotes growth and proliferation in many tissues throughout animal development. An important challenge is to identify how the Ras-Erk pathway alters cellular metabolism to drive growth. Here we report on the control of tRNA synthesis as growth effector of EGF/Ras/Erk signaling in Drosophila. I find that overexpression of oncogenic Ras (RasV12) leads to increased mRNA translation and protein content in Drosophila S2 cells, suggesting that Ras may promote growth through enhanced protein synthesis. The conventional view is that the Ras pathway functions by controlling translation initiation factor activity. However I have identified an alternate mechanism involving control of tRNA synthesis. My data suggest that overexpression of RasV12 or the activated versions of EGFR and the Raf1 in wing imaginal discs increases tRNA synthesis. Similarly, expression of RasV12 in S2 cells increases tRNA levels, while blocking Ras/Erk signaling using the MEK inhibitor, U0126 or RNAi reduces tRNA synthesis. We previously identified the RNA polymerase III (Pol III) factor, Brf, as regulator of cell and tissue growth in Drosophila. Here we show that knockdown of either Brf blocks the effects of Ras signaling on growth and proliferation in larval wing imaginal discs, adult midgut progenitor cells and adult intestinal stem cells. Several transcription factors have been shown to link Ras signaling to changes in mRNA expression and growth. I have identified Myc is required but not sufficient for Ras-induced cell proliferation and growth through tRNA synthesis. Previously we have shown that TOR signaling regulates protein synthesis through RNA Pol III repressor, Maf1. I found that Maf1 RNAi increases tRNA synthesis in S2 cells. In addition, the decrease in tRNA synthesis induced by the MEK inhibitor is blocked in the presence of Maf1 RNAi suggesting Maf1 is downstream of Ras signaling pathway. My data point to control of tRNA synthesis possibly through Myc and/or Maf1 as a new mechanisms by which Ras signaling enhances protein synthesis to promote cell and tissue growth. Citation Format: Shrivani Sriskanthadevan-Pirahas, Savraj S. Grewal. EGF/Ras/Erk signaling controls growth and proliferation through regulation of tRNA synthesis. [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 B13.