The translational landscape of mTOR signalling steers cancer initiation and metastasis
By A. Hsieh, Yi Liu, Merritt P. Edlind, Nicholas T. Ingolia, M. R. Janes, A. Sher, Evan Y. Shi, C. Stumpf, Carly Christensen, M. Bonham and 9 more. Nature, 2012
1,314 citations recorded by the source corpus.
The mammalian target of rapamycin (mTOR) kinase is a master regulator of protein synthesis that couples nutrient sensing to cell growth and cancer. However, the downstream translationally regulated nodes of gene expression that may direct cancer development are poorly characterized. Using ribosome profiling, we uncover specialized translation of the prostate cancer genome by oncogenic mTOR signalling, revealing a remarkably specific repertoire of genes involved in cell proliferation, metabolism and invasion. We extend these findings by functionally characterizing a class of translationally controlled pro-invasion messenger RNAs that we show direct prostate cancer invasion and metastasis downstream of oncogenic mTOR signalling. Furthermore, we develop a clinically relevant ATP site inhibitor of mTOR, INK128, which reprograms this gene expression signature with therapeutic benefit for prostate cancer metastasis, for which there is presently no cure. Together, these findings extend our understanding of how the ‘cancerous’ translation machinery steers specific cancer cell behaviours, including metastasis, and may be therapeutically targeted.
Subfields: Molecular Biology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/aa9e537e122b55a1e0d42692ae156d4204ddff6f
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Molecular Biology
- David M. Sabatini
- R. Shaw
- R. A. Saxton
- Michael Pollak
- C. Fraser
- Nahum Sonenberg
- K. Feoktistova
- Enkhee Tuvshintogs
In Pulmonary and Respiratory Medicine
Citations in the corpus
- mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype (2015, neutral): “Interestingly, global ribosome profiling has suggested that mTOR can control MAPKAPK2 translation 20,35 .”
- Glc-TOR signalling leads transcriptome reprogramming and meristem activation (2013, neutral): “Regulation of transcription (95) Miscellaneous (85) Protein folding (78) Cell wall synthesis (60) Metabolism (56) Signalling (47) RNA synthesis & processing (38) Transporter (37) Amino acid synthesis (31) Protein modification (30) Protein degradation (30) Nucleotide synthesis (29) TCA cycle & ETC (2”
- Small molecule inhibition of the autophagy kinase ULK1 and identification of ULK1 substrates (2015, methodology): “To activate endogenous ULK1, we treated MEFs with either amino acid starvationmedia (Earle’s balanced salt solution [EBSS]) or themTORATP-competitive inhibitors INK128 or AZD8055 (Chresta et al., 2010; Hsieh et al., 2012).”
- mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “Global ribosome footprinting analyses, however, revealed that, while acutemTOR inhibitionmoderately suppresses general mRNA translation, it most profoundly affects mRNAs containing pyrimidine-rich 50 TOP or ‘‘TOP-like’’ motifs, which includes most genes involved in protein synthesis (Hsieh et al., 2”