Editors' ChoiceCell Biology

New connections: Role of 4EBPs in controlling cell behavior

Sci. Signal.  26 Apr 2016:
Vol. 9, Issue 425, pp. ec101
DOI: 10.1126/scisignal.aaf9415

Cells can increase or decrease the synthesis of new proteins to accommodate changes in activity or in response to stress. Protein synthesis can be activated by the kinase mTOR through its phosphorylation and inhibition of eukaryotic translation initiation factor 4E-binding proteins (4EBPs). Two studies published in Science Signaling reveal central roles for 4EBP-restricted protein synthesis in two very different cellular contexts. Tudor et al. explored why a bad night’s sleep impairs learning and memory. They found that sleep deprivation in mice impaired memory, suppressed activation of the kinase complex mTORC1, and consequently reduced protein synthesis in hippocampal neurons. Restoring protein synthesis by increasing the amount of phosphorylated 4EBP2 protein in the hippocampus—a function normally performed by mTORC1—protected mice from the memory impairment caused by sleep deprivation. Hsieh et al. explored why some cells in prostate tumors are resistant to PI3K-AKT-mTOR pathway inhibitors. They found that cell type–specific resistance was mediated by the abundance of 4EBP1. Compared with basal cells, luminal prostate epithelial cells had increased abundance of 4EBP1, decreased protein synthesis rates, and decreased sensitivity to the mTOR inhibitor MLN0128. In both mice and patients with prostate cancer, treatment with a PI3K pathway inhibitor increased the proportion of luminal tumor cells that had high abundance of 4EBP1. Decreasing 4EBP1 abundance suppressed resistance to MLN0128, thus cotargeting 4EBP1 may improve therapeutic outcomes for prostate cancer patients. Studies of the regulation of translation are an area of interest for Science Signaling. These studies reveal unexpected complexity in the function of 4EBP proteins in the regulation of protein synthesis in both physiological and pathological contexts.

J. C. Tudor, E. J. Davis, L. Peixoto, M. E. Wimmer, E. van Tilborg, A. J. Park, S. G. Poplawski, C. W. Chung, R. Havekes, J. Huang, E. Gatti, P. Pierre, T. Abel, Sleep deprivation impairs memory by attenuating mTORC1-dependent protein synthesis. Sci. Signal. 9, ra41 (2016). [Abstract]

A. C. Hsieh, H. G. Nguyen, L. Wen, M. P. Edlind, P. R. Carroll, W. Kim, D. Ruggero, Cell type–specific abundance of 4EBP1 primes prostate cancer sensitivity or resistance to PI3K pathway inhibitors. Sci. Signal. 8, ra116 (2016). [Abstract]