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Regulation of mTOR by pharmacological activators of transcription factor Nrf2


Project Description

The mechanistic target of rapamycin (mTOR) is a kinase, which is the core component of two protein complexes termed mTOR complex 1 (mTORC1) and 2 (mTORC2), and has a fundamental role in the maintenance of cellular homeostasis. Dysregulation of mTOR is associated with a number of human diseases, such as type 2 diabetes, cancer, and neurodegeneration. Transcription factor Nrf2 allows adaptation and survival under conditions of stress, and is activated by a wide array of small molecules, which have a characteristic chemical signature: the ability to react with sulfhydryl groups. Using the human osteosarcoma cell line U2OS, we recently found that two Nrf2 activators, phenethyl isothiocyanate and bis(2-hydroxybenzylidene)acetone, inhibit mTOR. The aim of this project is to gain insights into the mechanism by which sulfhydryl-reactive Nrf2 activators inhibit mTOR, and characterize the downstream consequences. First, we will establish whether inhibition of mTOR is a common property of sulfhydryl-reactive Nrf2 activators by using compounds of distinct chemical classes, and test for the potential requirement of Nrf2 for mTOR inhibition. Second, we will determine whether inhibition of mTOR by these compounds is a general phenomenon by using a number of different cancer cell lines (neuroblastoma: SH-5YSY, lung: A549, colon: DLD-1; breast: MDA-MB-231). We will then examine the downstream consequences of mTOR inhibition by evaluating the phosphorylation levels of mTOR targets (such as p70 S6K and 4E-BP1), and markers of autophagy. We will also evaluate the effect of Nrf2 depletion (by siRNA) on the expression of mTOR by evaluating the levels of its mRNA. We will then perform rescue experiments by re-introducing ectopically expressed Nrf2. The project will involve cell culture, transfection, quantitative real-time PCR, immunoblotting, and immunofluorescence imaging.

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To apply please send a cover letter, curriculum vitae and two references to:

Funding Notes

Please note this is a self-funded PhD project

References

Saxton RA & Sabatini DM. mTOR Signaling in Growth, Metabolism, and Disease. Cell. 2017 Mar 9;168(6):960-976.

Dayalan Naidu S et al. Transcription Factors NRF2 and HSF1 Have Opposing Functions in Autophagy. Sci Rep. 2017 Sep 8;7(1):11023.

Dayalan Naidu S et al. Heat Shock Factor 1 Is a Substrate for p38 Mitogen-Activated Protein Kinases. Mol Cell Biol. 2016 Aug 26;36(18):2403-17.

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