Regulation of mTORC1 and its impact on gene expression at a glance

Abstract

The mechanistic (or mammalian) target of rapamycin (mTOR) is a kinase that regulates key cellular functions linked to the promotion of cell growth and metabolism. This kinase, which is part of two protein complexes termed mTOR complex 1 (mTORC1) and 2 (mTORC2), has a fundamental role in coordinating anabolic and catabolic processes in response to growth factors and nutrients. Of the two mTOR complexes, mTORC1 is by far the best characterized. When active, mTORC1 triggers cell growth and proliferation by promoting protein synthesis, lipid biogenesis, and metabolism, and by reducing autophagy. The fact that mTORC1 deregulation is associated with several human diseases, such as type 2 diabetes, cancer, obesity and neurodegeneration, highlights its importance in the maintenance of cellular homeostasis. Over the last years, several groups observed that mTORC1 inhibition, in addition to reducing protein synthesis, deeply affects gene transcription. Here, we review the connections between mTORC1 and gene transcription by focusing on its impact in regulating the activation of specific transcription factors including including STAT3, SREBPs, PPARγ, PPARα, HIF1α, YY1–PGC1α and TFEB. We also discuss the importance of these transcription factors in mediating the effects of mTORC1 on various cellular processes in physiological and pathological contexts.

The role of STAT3 in autophagy

“…9 Serine phosphorylation of STAT3 The literature suggests a modulatory role for Ser727 phosphorylation in STAT3 transcriptional activation, presumably through the enhanced recruitment of necessary transcriptional cofactors as occurs after the serine phosphorylation of STAT1. 21,30,31 The enzymes that catalyze the phosphorylation of STAT3 on S727 are numerous, including MTOR and MAPK1. 5,31,32 Studies have shown that STAT3 requires tyrosine and serine residues to be phosphorylated by independent protein kinase activities for the maximal activation of target gene transcription.…”

“…21,30,31 The enzymes that catalyze the phosphorylation of STAT3 on S727 are numerous, including MTOR and MAPK1. 5,31,32 Studies have shown that STAT3 requires tyrosine and serine residues to be phosphorylated by independent protein kinase activities for the maximal activation of target gene transcription. Yokogami et al showed that STAT3 Ser727 phosphorylation was inhibited by the MTOR inhibitor rapamycin during CNTF (ciliary neurotrophic factor) signaling and that the maximal activation of STAT3 in CNTF-stimulated neuroblastoma cells depends on serine phosphorylation.…”

Rapamycin reduces fibroblast proliferation without causing quiescence and induces STAT5A/B-mediated cytokine production

“…Although it primarily inhibits TORC1, high concentrations or chronic exposure of rapamycin have also been reported to inhibit TORC2. [14][15][16][17] This compound has attracted a great deal of attention due to its proposed ability to mimic caloric restriction, resulting in decreased protein translation, increased autophagy and increased health and lifespan. [18][19][20][21][22] These benefits were observed in both mice fed high-fat diets 20 and older mice 23 when fed rapamycin.…”

IGF-1 regulation of key signaling pathways in bone

“…mTORC2 (rapamycin insensitive during acute exposure), which consists of mTOR, Rictor (rapamycin insensitive companion of mTOR), mLST8/GbL, mSIN1 (mammalian stress-activated protein kinase-interacting protein 1) and PROTOR (protein observed with Rictor), can activate AKT by phosphorylating it at Ser 473 and can therefore inhibit FoxO1. 15,16 There are no conditional mouse models that have targeted the mTOR signaling pathway in osteoblasts.…”