Carson Thoreen, PhD
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Research Summary
Our lab is working to understand the molecular basis of translational control mechanisms, how signaling pathways engage them, and how defects can lead to disease. A major focus of our research is the mTOR signaling pathway, a sensor of the cellular nutrient status and a master regulator of cell growth. This pathway can elicit profound changes in the translational machinery, and is deregulated is a wide variety of diseases, including cancer, metabolic disease and neurologic disorders. We are using biochemical, bioinformatic and chemical biology approaches to understand the molecular basis of mTOR-regulated translational control mechanisms, how they are employed for normal physiologic purposes in nutrient-sensitive tissues, and how they are exploited by tumor cells to support unrestricted growth.
Specialized Terms: Growth control; RNA; Translation; Cancer biology; Signaling; Biochemistry; Bioinformatics; Metabolism
Extensive Research Description
The mammalian target of rapamycin (mTOR) pathway is an evolutionarily conserved master regulator of cell growth with important roles in metabolism, aging and cancer. The pathway senses nutrient and growth signals, and responds to these by regulating many major metabolic pathways, but particularly mRNA translation. We found that acute inhibition of mTOR selectively inhibits the translation of large class of mRNAs containing a terminal oligopyrimidine (TOP) motif at the 5’ terminus by disrupting the mRNA cap-binding complex, eIF4F. The mTOR pathway has many additional targets in the translational machinery, but the functional significance of these is unknown. We want to understand how mTOR-regulated translational mechanisms work in molecular detail, what features in mRNAs determine their dependence on mTOR activity, and how these controls are employed physiologically.
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Research Interests
Biochemistry; Metabolism; Physiology; Translations
Selected Publications
- mRNA 5′ terminal sequences drive 200-fold differences in expression through effects on synthesis, translation and decayvan den Elzen A, Watson M, Thoreen C. mRNA 5′ terminal sequences drive 200-fold differences in expression through effects on synthesis, translation and decay. PLOS Genetics 2022, 18: e1010532. PMID: 36441824, PMCID: PMC9731452, DOI: 10.1371/journal.pgen.1010532.
- Roadblock-qPCR: a simple and inexpensive strategy for targeted measurements of mRNA stabilityWatson M, Park Y, Thoreen C. Roadblock-qPCR: a simple and inexpensive strategy for targeted measurements of mRNA stability. RNA 2020, 27: 335-342. PMID: 33288682, PMCID: PMC7901842, DOI: 10.1261/rna.076885.120.
- La-related protein 1 (LARP1) repression of TOP mRNA translation is mediated through its cap-binding domain and controlled by an adjacent regulatory regionPhilippe L, Vasseur JJ, Debart F, Thoreen CC. La-related protein 1 (LARP1) repression of TOP mRNA translation is mediated through its cap-binding domain and controlled by an adjacent regulatory region. Nucleic Acids Research 2017, 46: gkx1237-. PMID: 29244122, PMCID: PMC5814973, DOI: 10.1093/nar/gkx1237.
- mTORC1 Balances Cellular Amino Acid Supply with Demand for Protein Synthesis through Post-transcriptional Control of ATF4Park Y, Reyna-Neyra A, Philippe L, Thoreen CC. mTORC1 Balances Cellular Amino Acid Supply with Demand for Protein Synthesis through Post-transcriptional Control of ATF4. Cell Reports 2017, 19: 1083-1090. PMID: 28494858, PMCID: PMC5811220, DOI: 10.1016/j.celrep.2017.04.042.
- ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAPMuranen T, Selfors L, Hwang J, Gallegos L, Coloff J, Thoreen C, Kang S, Sabatini D, Mills G, Brugge J. ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP. Cancer Research 2016, 76: 7168-7180. PMID: 27913436, PMCID: PMC5161652, DOI: 10.1158/0008-5472.can-16-0155.
- Abstract PR03: The Hippo pathway effector YAP1 contributes to escape from proliferation arrest under chronic PI3K/mTOR inhibitionMuranen T, Selfors L, Thoreen C, Gallegos L, Coloff J, Mills G, Brugge J. Abstract PR03: The Hippo pathway effector YAP1 contributes to escape from proliferation arrest under chronic PI3K/mTOR inhibition. Molecular Cancer Therapeutics 2015, 14: pr03-pr03. DOI: 10.1158/1538-8514.pi3k14-pr03.
- A unifying model for mTORC1-mediated regulation of mRNA translationThoreen CC, Chantranupong L, Keys HR, Wang T, Gray NS, Sabatini DM. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 2012, 485: 109-113. PMID: 22552098, PMCID: PMC3347774, DOI: 10.1038/nature11083.
- An ATP-competitive Mammalian Target of Rapamycin Inhibitor Reveals Rapamycin-resistant Functions of mTORC1*Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, Reichling LJ, Sim T, Sabatini DM, Gray NS. An ATP-competitive Mammalian Target of Rapamycin Inhibitor Reveals Rapamycin-resistant Functions of mTORC1*. Journal Of Biological Chemistry 2009, 284: 8023-8032. PMID: 19150980, PMCID: PMC2658096, DOI: 10.1074/jbc.m900301200.
- mSin1 Is Necessary for Akt/PKB Phosphorylation, and Its Isoforms Define Three Distinct mTORC2sFrias M, Thoreen C, Jaffe J, Schroder W, Sculley T, Carr S, Sabatini D. mSin1 Is Necessary for Akt/PKB Phosphorylation, and Its Isoforms Define Three Distinct mTORC2s. Current Biology 2006, 16: 1865-1870. PMID: 16919458, DOI: 10.1016/j.cub.2006.08.001.
- Huntingtin aggregates ask to be eatenThoreen C, Sabatini D. Huntingtin aggregates ask to be eaten. Nature Genetics 2004, 36: 553-554. PMID: 15167929, DOI: 10.1038/ng0604-553.
- A proteomics approach to understanding protein ubiquitinationPeng J, Schwartz D, Elias J, Thoreen C, Cheng D, Marsischky G, Roelofs J, Finley D, Gygi S. A proteomics approach to understanding protein ubiquitination. Nature Biotechnology 2003, 21: 921-926. PMID: 12872131, DOI: 10.1038/nbt849.
- Evaluation of Multidimensional Chromatography Coupled with Tandem Mass Spectrometry (LC/LC−MS/MS) for Large-Scale Protein Analysis: The Yeast ProteomePeng J, Elias J, Thoreen C, Licklider L, Gygi S. Evaluation of Multidimensional Chromatography Coupled with Tandem Mass Spectrometry (LC/LC−MS/MS) for Large-Scale Protein Analysis: The Yeast Proteome. Journal Of Proteome Research 2002, 2: 43-50. PMID: 12643542, DOI: 10.1021/pr025556v.
- Automation of Nanoscale Microcapillary Liquid Chromatography−Tandem Mass Spectrometry with a Vented ColumnLicklider L, Thoreen C, Peng J, Gygi S. Automation of Nanoscale Microcapillary Liquid Chromatography−Tandem Mass Spectrometry with a Vented Column. Analytical Chemistry 2002, 74: 3076-3083. PMID: 12141667, DOI: 10.1021/ac025529o.
- Integration of cytogenetic landmarks into the draft sequence of the human genomeBAC Resource Consortium T, Cheung V, Nowak N, Jang W, Kirsch I, Zhao S, Chen X, Furey T, Kim U, Kuo W, Olivier M, Conroy J, Kasprzyk A, Massa H, Yonescu R, Sait S, Thoreen C, Snijders A, Lemyre E, Bailey J, Bruzel A, Burrill W, Clegg S, Collins S, Dhami P, Friedman C, Han C, Herrick S, Lee J, Ligon A, Lowry S, Morley M, Narasimhan S, Osoegawa K, Peng Z, Plajzer-Frick I, Quade B, Scott D, Sirotkin K, Thorpe A, Gray J, Hudson J, Pinkel D, Ried T, Rowen L, Shen-Ong G, Strausberg R, Birney E, Callen D, Cheng J, Cox D, Doggett N, Carter N, Eichler E, Haussler D, Korenberg J, Morton C, Albertson D, Schuler G, de Jong P, Trask B. Integration of cytogenetic landmarks into the draft sequence of the human genome. Nature 2001, 409: 953-958. PMID: 11237021, PMCID: PMC7845515, DOI: 10.1038/35057192.