Insights into the regulation of mTOR signaling and the consequences of pharmacological inhibition
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2008.
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| Format: | Thesis |
| Language: | eng |
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Massachusetts Institute of Technology
2009
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| Online Access: | http://hdl.handle.net/1721.1/45310 |
| _version_ | 1826214150412435456 |
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| author | Thoreen, Carson Cornell |
| author2 | David M. Sabatini. |
| author_facet | David M. Sabatini. Thoreen, Carson Cornell |
| author_sort | Thoreen, Carson Cornell |
| collection | MIT |
| description | Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2008. |
| first_indexed | 2024-09-23T16:00:37Z |
| format | Thesis |
| id | mit-1721.1/45310 |
| institution | Massachusetts Institute of Technology |
| language | eng |
| last_indexed | 2024-09-23T16:00:37Z |
| publishDate | 2009 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/453102019-04-10T23:21:11Z Insights into the regulation of mTOR signaling and the consequences of pharmacological inhibition Thoreen, Carson Cornell David M. Sabatini. Massachusetts Institute of Technology. Dept. of Biology. Massachusetts Institute of Technology. Dept. of Biology. Biology. Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2008. Includes bibliographical references. Cells have evolved a highly tuned system for driving growth in response to the right cues. Permissive signals initiate a cascade of events that send nutrient transporters to the membrane, suppress apoptosis, boost protein synthesis, and adjust metabolic processes to fuel the cell's energy demands. Increases in cell growth are often coordinated with cell division, though the two programs can be decoupled. The TOR complexes, TORCI and TORC2, are central regulators of cell growth and share the serine/threonine TOR kinase as their catalytic domain. In mammals, the TORC2 homolog mTORC2 is activated by growth factors through the lipid kinase PI3K, and is a primary effector for many of its functions, including regulation of the proliferation and survival kinase Akt/PKB. Activation of PI3K also leads to activation of mTORC1. Unlike mTORC2, mTORC1 is equally dependent on nutrient availability, and connects to the protein translation machinery through its substrates S6K and 4E-BP1. Additionally, S6K can suppress insulin signaling, establishing a negative feedback loop to PI3K. Consistent with its role in cell growth, derangements in mTOR signaling are increasingly associated with cancer and, more surprisingly, metabolic diseases. In the work described here, we have investigated the mechanism through which insulin activates mTORC1 and identified the protein PRAS40 as a growth factor-regulated inhibitor and mTORC1 component. PRAS40 cooperates with rheb, an mTORC1 activator, to regulate growth factor signaling through the pathway. We have also developed a potent and selective mTORC1/2 small molecule inhibitor and used this to probe the role of mTOR signaling in tumor cell growth and proliferation. Through this, we have identified common genetic mutations that determine sensitivity to mTOR inhibition and suggest a novel therapeutic anticancer strategy. by Carson Cornell Thoreen. Ph.D. 2009-04-29T17:23:52Z 2009-04-29T17:23:52Z 2008 2008 Thesis http://hdl.handle.net/1721.1/45310 313750465 eng M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission. http://dspace.mit.edu/handle/1721.1/7582 179 p. application/pdf Massachusetts Institute of Technology |
| spellingShingle | Biology. Thoreen, Carson Cornell Insights into the regulation of mTOR signaling and the consequences of pharmacological inhibition |
| title | Insights into the regulation of mTOR signaling and the consequences of pharmacological inhibition |
| title_full | Insights into the regulation of mTOR signaling and the consequences of pharmacological inhibition |
| title_fullStr | Insights into the regulation of mTOR signaling and the consequences of pharmacological inhibition |
| title_full_unstemmed | Insights into the regulation of mTOR signaling and the consequences of pharmacological inhibition |
| title_short | Insights into the regulation of mTOR signaling and the consequences of pharmacological inhibition |
| title_sort | insights into the regulation of mtor signaling and the consequences of pharmacological inhibition |
| topic | Biology. |
| url | http://hdl.handle.net/1721.1/45310 |
| work_keys_str_mv | AT thoreencarsoncornell insightsintotheregulationofmtorsignalingandtheconsequencesofpharmacologicalinhibition |