Expression of mTOR in normal and pathological conditions

Abstract

The mechanistic/mammalian target of rapamycin (mTOR), a protein discovered in 1991, integrates a complex pathway with a key role in maintaining cellular homeostasis. By comprising two functionally distinct complexes, mTOR complex 1 (mTORC1) and mTORC2, it is a central cellular hub that integrates intra- and extracellular signals of energy, nutrient, and hormone availability, modulating the molecular responses to acquire a homeostatic state through the regulation of anabolic and catabolic processes. Accordingly, dysregulation of mTOR pathway has been implicated in a variety of human diseases. While major advances have been made regarding the regulators and effectors of mTOR signaling pathway, insights into the regulation of mTOR gene expression are beginning to emerge. Here, we present the current available data regarding the mTOR expression regulation at the level of transcription, translation and mRNA stability and systematize the current knowledge about the fluctuations of mTOR expression observed in several diseases, both cancerous and non-cancerous. In addition, we discuss whether mTOR expression changes can be used as a biomarker for diagnosis, disease progression, prognosis and/or response to therapeutics. We believe that our study will contribute for the implementation of new disease biomarkers based on mTOR as it gives an exhaustive perspective about the regulation of mTOR gene expression in both normal and pathological conditions.

Keywords: mTOR biomarker; mTOR expression; mTOR expression cancer; mTOR expression disease; mTOR mRNA stability; mTOR transcriptional regulation; mTOR translation regulation.

Fig. 1

Signals, pathways, targets, and outputs of the mTOR signalling. mTOR is a protein kinase that complexes with several proteins composing the mTOR complex 1 (mTORC1) and mTORC2. Both are activated by growth factors and mTORC1 also depends on amino acids for its translocation into the lysosome membrane where it becomes fully activated. These processes involve the activation of the Rag GTPases Rag A or Rag B and Rag C or D complexed with Ragulator complex in addition to the Ras homolog enriched in brain (RHEB). Additional signals that result in mTORC1 activation include insulin and inflammation, that act through the insulin-like growth factor-1 (IGF-1)/AKT and the TNF/Tuberous Sclerosis Complex (TSC) axis, respectively. On the other hand, inactivation of mTORC1 occurs under stress conditions, such as energy starvation, a process dependent on AMPK; hypoxia, through upregulation of REDD1, endoplasmatic reticulum stress (UPR) by upregulation of Sestrin 2 (SESN2); and DNA damage, by activation of the p53 transcriptional program. mTORC2 becomes activated in the plasma and mitochondrial membranes, a subpopulation of endosomal vesicles and in the nucleus, through site-specific processes. Each complex has a plethora of substrates, such as but not exclusively 4E-binding proteins (4E-BP), S6 kinases (S6K), unc-51-like kinase (ULK1) and Transcription factor EB (TFEB) for mTORC1 and glucocorticoid-induced kinases (SGK), protein kinase C (PKC) and AKT for mTORC2. The main biological processes regulated by mTORC1 include protein, lipid and nucleotides synthesis, metabolism and autophagy; and cytoskeleton reorganization, glucose homeostasis and metabolism for mTORC2, whose activation results in cell survival, growth, proliferation and migration

Fig. 2

Regulation of mTOR transcription. Amino acids increase mTOR transcription through induction of binding of transcriptional activators such as Nuclear Receptor Co-Activator 5 (NCOA5), Purine-Rich Element Binding Protein B (PURB), cyclin-dependent kinase substrate 1 (NUCKS1), and nuclear factor of kB (NFkB) to the mTOR promoter. In addition, amino acids induce the degradation of AT-rich interaction domain 1 A (ARID1A) and ARID1B, which result in increased mTOR transcription, through relieve of the inhibitory effect of H3K27ac, an epigenetic modified histone that marks for active enhancers; and the reversal of the inhibitory effect of ARID1B on mTOR promoter, respectively. The binding of H3K27ac to mTOR is further regulated by ARID4B and Brahma-related gene 1 (BRG1), that bind themselves to the promoter of mTOR in an amino acid-dependent manner. BRG1 additionally relieves the inhibitory effect of H3K27me3 on mTOR transcription. Other inducers of mTOR transcription upon amino acid stimulation, particularly, taurine, include the epigenetic marker for promoter activation H3K4Me3 and Cullin 5 (Cul5), an ubiquitin ligase that is highly expressed in mammary gland tissues in the lactation stage

Fig. 3

mTOR is translated in a cap-independent manner. mTOR 5’UTR adopts a highly folded and evolutionary conserved structure, that is capable to directly bind to the 40 S ribosomal subunit in the absence of any initiation factor. This RNA scaffold assists cap-independent translation of mTOR, allowing sustained mTOR protein levels in translational inhibitory conditions (hypoxia). Cap-independent translation of mTOR occurs both in normal and stress conditions and is necessary for mTOR function