Abstract B11: Oncogenic KRAS regulates 4E-BP1, a repressor of cap-dependent translation, independently of growth factor activity

Abstract

Abstract Oncogenic mutations in K-Ras often occur at high frequencies in human cancer resulting in the sustained activation of the ERK1/2 mitogen-activated protein kinase (MAPK) signaling pathway. However, the unique dependencies on upstream or downstream oncogenic signaling amongst the mutant K-Ras proteins remains elusive and often masked by the remaining wild-type allele, other Ras isoforms, or additional secondary genetic alterations. Thus, we employed an isogenic mouse embryonic fibroblast (MEFs) system devoid of H-, N-, and K-Ras alleles and reconstituted with a single Ras isoform to examine the dependencies of growth factors on K-Ras mediated control of translational regulation. Although oncogenic K-Ras G12D and G12V mutant MEF lines proliferated at twice the rate of K-Ras4b wild-type MEF cells, growth factor deprivation led to a cytostatic effect on the proliferation of all MEF lines. Analysis of signaling downstream of K-Ras revealed that phosphorylation of 4E-BP1, eIF4E, and ERK1/2 occurred in a growth factor-independent manner, which stood in contrast to the substantive effects of growth factor inhibition on AKT, p70S6K, and ribosomal protein S6 phosphorylation. Moreover, growth factor deprivation resulted in a marginal decrease of global protein synthesis with negligible effects on cap-dependent translation initiation in all K-Ras MEF cell lines. Taken together, these data suggest that oncogenic K-Ras signaling regulates 4E-BP1 phosphorylation independently of growth factor and mTORC1/2 effects. Citation Format: Jillian M. Silva, Rachel K. Bagni, Davide Ruggero, Frank McCormick. Oncogenic KRAS regulates 4E-BP1, a repressor of cap-dependent translation, independently of growth factor activity. [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 B11.