Activation of a Metabolic Gene Regulatory Network Downstream of mTOR Complex 1

Abstract

Aberrant activation of the mammalian target of rapamycin complex 1 (mTORC1) is a common molecular event in a variety of pathological settings, including genetic tumor syndromes, cancer, and obesity. However, the cell intrinsic consequences of mTORC1 activation remain poorly defined. Through a combination of unbiased genomic, metabolomic, and bioinformatic approaches, we demonstrate that mTORC1 activation is sufficient to stimulate specific metabolic pathways, including glycolysis, the oxidative arm of the pentose phosphate pathway, and de novo lipid biosynthesis. This is achieved through the activation of a transcriptional program affecting metabolic gene targets of hypoxia-inducible factor (HIF1α) and sterol regulatory element-binding protein (SREBP1 and SREBP2). We find that SREBP1 and 2 promote proliferation downstream of mTORC1, and the activation of these transcription factors is mediated by S6K1. Therefore, in addition to promoting protein synthesis, mTORC1 activates specific bioenergetic and anabolic cellular processes that are likely to contribute to human physiology and disease.

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

“…Hyperactivity of mTORC1 is sufficient to increase HK-II expression 52 and a recent comprehensive and unbiased analysis also supports mTORC1-mediated HK-II upregulation and further demonstrated that mTORC1 signaling activates the genes encoding nearly every step of glycolysis. 53 Hypoxia-inducible factor 1 (HIF-1) is a transcription factor. The α-subunit of HIF-1 (HIF-1α) is stabilized under hypoxic conditions, leading to the activation of a transcriptional program to adapt to the lack of oxygen.…”

Myelination and mTOR

“…In SCs, but not in OLs, the transcription factor RXRγ was shown to be transcriptionally regulated by mTORC1 and to control, in turn, the transcription of SREBP1c downstream of mTORC1 (Lebrun‐Julien et al, 2014; Norrmén et al, 2014). Differently from other cell types (Düvel et al, 2010; Owen et al, 2012), the mTORC1 target S6K is probably not majorly involved in regulating SREBPs. Thus, myelinating cells seem to possess specific mechanisms to regulate SREBPs and the expression of enzymes for lipid synthesis, with the additional twist that these mechanisms are probably different between SCs and OLs.…”

“…Subsequently, mature SREBPs induce the expression of several enzymes involved in fatty acid and cholesterol synthesis (Porstmann et al, 2008). Although the exact mechanisms are not yet defined, S6K1 has been implicated in this process (Düvel et al, 2010; Owen et al, 2012). In addition, mTORC1 was shown to modulate the actions of mature SREBPs by regulating the localization of lipin‐1.…”

“…In the absence of Rheb1 or Raptor, a reduction in OLs and an accumulation of OPCs were detected (Bercury et al, 2014; Zou et al, 2014), in line with a previous report in which rapamycin inhibited the progression of O4‐positive late OPCs to GalC‐positive immature OLs in vitro (Tyler et al, 2009). Besides its direct regulation of metabolic reactions, mTORC1 has a profound impact on the cell transcriptome (Düvel et al, 2010) and controls several transcription factors directly or via its downstream targets. Thus, it is possible that also one or more transcription factors with roles in OL differentiation are acting downstream of mTORC1.…”

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

“…mTORC1 and MYC have overlapping functions, including stimulating effects on cell growth and proliferation, ribosome biogenesis, and protein synthesis. In addition, mTORC1 induces oxidative phosphorylation by facilitating YY1/PGC1α complex formation (Cunningham et al , 2007) and supports aerobic glycolysis (Duvel et al , 2010). In the Eμ‐Myc mouse model, mTORC1 activation was shown to accelerate lymphomagenesis by inhibiting Myc‐induced apoptosis through translational upregulation of the anti‐apoptotic protein myeloid cell leukemia 1 (Mcl1; Mills et al , 2008), suggesting a collaboration of Myc and mTORC1 in tumor initiation.…”