Role of GLUT1 in the Mammalian Target of Rapamycin Pathway: Mechanisms of Regulation.
dc.contributor.author | Buller, Carolyn L. | en_US |
dc.date.accessioned | 2010-08-27T15:09:27Z | |
dc.date.available | NO_RESTRICTION | en_US |
dc.date.available | 2010-08-27T15:09:27Z | |
dc.date.issued | 2010 | en_US |
dc.date.submitted | en_US | |
dc.identifier.uri | https://hdl.handle.net/2027.42/77734 | |
dc.description.abstract | GLUT1-mediated glucose transport is a highly regulated process and is dependent on a variety of signaling events. The glycogen synthase kinase (GSK)-3/tuberous sclerosis(TSC)/mammalian target of rapamycin (mTOR) signaling pathway has been implicated in regulation of glucose transport, but the mechanisms have not been well defined. Increased expression of GLUT1 in kidney cells may play a role in the development of diabetic nephropathy, and there is increased mTOR activation in animal models of diabetes. Therefore, I sought to test the hypothesis that the GSK-3/TSC2/mTOR pathway can activate GLUT1 expression and may be subject to positive feedback by GLUT1 expression and resultant glucose uptake. In multiple cell types, GLUT1 expression and resultant glucose uptake were found to be enhanced through a GSK3/TSC/mTOR signaling pathway. In addition, overexpression of GLUT1 induced mTOR activation in both acute and chronic kidney mesangial cell culture systems and in kidney glomerular cells in vivo. Surprisingly, the GLUT1 stimulation of mTOR occurred through a Tuberous Sclerosis Comples (TSC) and AMP kinase independent pathway and appeared to involve GLUT1 stimulated release of the mTOR regulator, Rheb, from the glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), allowing it to associate and activate mTOR. Together, these data demonstrate that GLUT1 expression and glucose uptake are regulated by a GSK-3/TSC2/mTOR pathway, and that increased GLUT1 expression and glucose uptake can activate mTORC1 independently of TSC2 and AMPK. | en_US |
dc.format.extent | 909530 bytes | |
dc.format.extent | 1373 bytes | |
dc.format.mimetype | application/octet-stream | |
dc.format.mimetype | text/plain | |
dc.language.iso | en_US | en_US |
dc.subject | GLUT1 and MTORC1 | en_US |
dc.title | Role of GLUT1 in the Mammalian Target of Rapamycin Pathway: Mechanisms of Regulation. | en_US |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Molecular and Integrative Physiology | en_US |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | en_US |
dc.contributor.committeemember | Brosius III, Frank C. | en_US |
dc.contributor.committeemember | Barald, Kate F. | en_US |
dc.contributor.committeemember | Fingar, Diane C. | en_US |
dc.contributor.committeemember | Kretzler, Matthias | en_US |
dc.contributor.committeemember | Myers Jr., Martin G | en_US |
dc.subject.hlbsecondlevel | Molecular, Cellular and Developmental Biology | en_US |
dc.subject.hlbsecondlevel | Physiology | en_US |
dc.subject.hlbtoplevel | Health Sciences | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/77734/1/cbuller_1.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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