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You searched for +publisher:"University of North Carolina" +contributor:("Bailey, Sean"). One record found.

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University of North Carolina

1. Bailey, Sean. Inhibition of compensatory survival and proliferative pathway activation induced by mTOR inhibition in renal cell carcinoma.

Degree: 2014, University of North Carolina

The mammalian target of rapamycin (mTOR) is a key regulator of tumor progression in a variety of cancers and has been shown to be dysregulated in renal cell carcinoma (RCC). mTOR exists in two independent complexes. The mTORC1 complex consists of mTOR, Raptor, and GβL, while the mTORC2 complex consists of mTOR, Rictor, and GβL. Currently there are two FDA approved rapamycin derivatives (rapalogs) for the treatment of advanced renal cell carcinoma (RCC). Allosteric mTOR inhibition (i.e. rapalogs) results in the release of negative feedback inhibition on the PI3K/AKT survival-signaling pathway as well as upregulates the metabolically protective process known as autophagy. Furthermore, catalytic mTOR inhibitors attenuate mTORC1 downstream signaling nodes more completely, but also diminishes mTORC2 mediated AKT survival signals induced by allosteric mTOR inhibitors. Additionally, it has been demonstrated, that mTOR inhibition results in activation of the MEK/MAPK signaling cascade. Based on this information, we wished to interrogate the molecular and biological consequences of inhibiting mTOR pharmacologically and genetically in the context of RCC. We first asked what was the effect of allosteric versus catalytic mTOR inhibition in several conventional human RCC cell lines and novel patient derived xenograft cell lines on mTORC1 and mTORC2 signaling. We saw that only 1) catalytic mTOR inhibition decreased pAKTS473 expression, 2) that both allosteric and catalytic mTOR inhibition increase pERKT202/Y204 expression, and 3) combined MEK and mTOR inhibition induced cell death better than single pathway inhibition alone. Finally, we noted that hierarchal clustering of KIRC_TCGA RPPA (reverse phase protein array) data by markers of mTOR and MEK activation revealed subclasses respective to mTOR and MEK/ERK signaling with significant differences in clinical outcome. We next asked how allosteric versus catalytic mTOR inhibition affected the metabolically conserved process known as autophagy. While both allosteric and catalytic inhibition increased autophagic flux; catalytic mTOR inhibition did so to a greater degree. To determine if this was due to catalytic mTOR inhibitors' ability to attenuate mTORC2 signaling we assessed autophagic flux in cell lines stably expressing shRNAs targeting Raptor or Rictor, essential components for mTORC1 and mTORC2 signaling, respectively. Knock-down of Raptor results in an increase in autophagic flux, however knock-down of Rictor also increases autophagic flux demonstrating that the increased autophagic flux induced by catalytic mTOR inhibition is partly due to inhibition of mTORC2. Finally, we show that catalytic mTOR inhibition in conjunction with autophagy inhibition decreases cellular proliferation while augmenting apoptosis. Together these data support that there are differences in levels of activation of compensatory survival pathways in the context of allosteric and catalytic mTOR inhibition. Advisors/Committee Members: Bailey, Sean, Kim, William, Baldwin, Albert, Bautch, Victoria, Davis, Ian, Rathmell, W. Kimryn.

Subjects/Keywords: Molecular biology; Genetics; School of Medicine; Curriculum in Genetics and Molecular Biology

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APA (6th Edition):

Bailey, S. (2014). Inhibition of compensatory survival and proliferative pathway activation induced by mTOR inhibition in renal cell carcinoma. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:3ecdd41c-8862-4504-a14a-8ead22d81d74

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Bailey, Sean. “Inhibition of compensatory survival and proliferative pathway activation induced by mTOR inhibition in renal cell carcinoma.” 2014. Thesis, University of North Carolina. Accessed September 22, 2020. https://cdr.lib.unc.edu/record/uuid:3ecdd41c-8862-4504-a14a-8ead22d81d74.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Bailey, Sean. “Inhibition of compensatory survival and proliferative pathway activation induced by mTOR inhibition in renal cell carcinoma.” 2014. Web. 22 Sep 2020.

Vancouver:

Bailey S. Inhibition of compensatory survival and proliferative pathway activation induced by mTOR inhibition in renal cell carcinoma. [Internet] [Thesis]. University of North Carolina; 2014. [cited 2020 Sep 22]. Available from: https://cdr.lib.unc.edu/record/uuid:3ecdd41c-8862-4504-a14a-8ead22d81d74.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Bailey S. Inhibition of compensatory survival and proliferative pathway activation induced by mTOR inhibition in renal cell carcinoma. [Thesis]. University of North Carolina; 2014. Available from: https://cdr.lib.unc.edu/record/uuid:3ecdd41c-8862-4504-a14a-8ead22d81d74

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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