Genome-Wide Analysis of Translational Control in Tuberous Sclerosis Complex.

摘要

The TSC1/TSC2 complex integrates multiple cues to regulate protein translation and cell growth via mammalian target of rapamycin complex I (mTORC1). Loss of TSC functions leads to constitutive activation of mTORC1 and uncontrolled mRNA translation. The goal of this res earch project to elucidate cis -regulatory elements and trans -acting factors in TSC-mTORC1- mediated translational regulation. We have discovered that the stress -induced preferential translation of Hsp70 mRNA is deficient in cells lacking TSC2. This finding provides a plausible mechanism about how persistent mTOR signaling favors the development of various pathologies of TSC by attenuating stress resistance. We recently discovered that TSC -mTORC1 increased the yield of protein synthesis at the expense of protein quality. By harnessing the power of ribosome profiling, we also discovered post-initiation ribosomal pausing that is subject to TSC-mTORC1 regulation. In addition, we have established a novel approach called Global Translation Initiation sequencing (GTI-seq) to investigate alternative translation. These studies are significant because TSC- mTORC1-controlled alternative translation initiation has never been defined.