Background: mTORC1 plays an important role in the regulation of TOP mRNA translation. Results: LARP1 is a target of mTORC1 that associates with TOP mRNAs via their 5ЈTOP motif to repress their translation. Conclusion: LARP1 represses TOP mRNA translation downstream of mTORC1. Significance: We elucidate an important novel signaling pathway downstream of mTORC1 that controls the production of ribosomes and translation factors in eukaryotic cells.
Translational control of gene expression plays a key role during the early phases of embryonic development. Here we describe a transcriptional regulator of mouse embryonic stem cells (mESCs), Yin-yang 2 (YY2), that is controlled by the translation inhibitors, Eukaryotic initiation factor 4E-binding proteins (4E-BPs). YY2 plays a critical role in regulating mESC functions through control of key pluripotency factors, including Octamer-binding protein 4 (Oct4) and Estrogen-related receptor-β (Esrrb). Importantly, overexpression of YY2 directs the differentiation of mESCs into cardiovascular lineages. We show that the splicing regulator Polypyrimidine tractbinding protein 1 (PTBP1) promotes the retention of an intron in the 5′-UTR of Yy2 mRNA that confers sensitivity to 4E-BP-mediated translational suppression. Thus, we conclude that YY2 is a major regulator of mESC self-renewal and lineage commitment and document a multilayer regulatory mechanism that controls its expression.mRNA translation | 4E-BPs | PTBP | embryonic stem cell | YY2
The circadian (~24 h) clock is continuously entrained (reset) by ambient light so that endogenous rhythms are synchronized with daily changes in the environment. Light-induced gene expression is thought to be the molecular mechanism underlying clock entrainment. mRNA translation is a key step of gene expression, but how clock entrainment is controlled at the mRNA translation level is not understood. Here we report that a light- and circadian clock-regulated MAPK/MNK pathway leads to phosphorylation of the cap-binding protein eIF4E in the mouse suprachiasmatic nucleus (SCN) of the hypothalamus, the locus of the master circadian clock in mammals. Phosphorylation of eIF4E specifically promotes translation of Period (Per) 1 and 2 mRNAs and increases the abundance of basal and inducible PER proteins, which facilitates circadian clock resetting and precise timekeeping. Together, these results highlight a critical role for light-regulated translational control in the physiology of the circadian clock.
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