GLUT1 enhances mTOR activity independently of TSC2 and AMPK

Buller, Carolyn L.; Heilig, Charles W.; Brosius, Frank C.

doi:10.1152/ajprenal.00472.2010

Cited by 56 publications

(48 citation statements)

References 42 publications

(64 reference statements)

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“…Decreased mTOR activity is associated with slowing the aging process and increasing lifespan. This signal network was recently corroborated by studies involving differential expression of GLUT1 (for, GLUcose Transporter 1) [158], which is the low Km transporter. With a Km appropriately 0.1 mM and blood plasma glucose at about 5 mM, glucose is free to enter the cell.…”

Section: Pi3k/akt/mtor Signalingmentioning

confidence: 69%

Functional Diversity

Seidler

2012

GAPDH: Biological Properties and Diversity

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There is increasing evidence to support a gene economy model that is fully based on the principles of evolution in which a limited number of proteins does not necessarily reflect a finite number of biochemical processes. The concept of 'gene sharing' proposes that a single protein can have alternate functions that are typically attributed to other proteins. GAPDH appears to play this role quite well in that it exhibits more than one function. GAPDH represents the prototype for this new paradigm of protein multi-functionality. The chapter discusses the diverse functions of GAPDH among three broad categories: cell structure, gene expression and signal transduction. Protein function is curiously re-specified given the cell's unique needs. GAPDH provides the cell with the means of linking metabolic activity to various cellular processes. While interpretations may often lead to GAPDH's role in meeting focal energy demands, this chapter discusses several other very distinct GAPDH functions (i.e. membrane fusogenic properties) that are quite different from its ability to catalyze oxidative phosphorylation of the triose, glyceraldehyde 3-phosphate. It is suggested that a single protein participates in multiple processes in the structural organization of the cell, controls the transmission of genetic information (i.e. GAPDH's involvement may not be finite) and mediates intracellular signaling.

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Section: Pi3k/akt/mtor Signalingmentioning

confidence: 69%

Functional Diversity

Seidler

2012

GAPDH: Biological Properties and Diversity

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“…GLUT1 has been shown to enhance mTOR activity independent of AMPK (Buller et al, 2011), and mTOR signalling can also increase translation of proteins including GLUT1 (Taha et al, 1999). Hence, the combined elevated expression of both GLUT1 and mTOR signalling in the presence of lower glucose levels is plausible.…”

Section: Tablementioning

confidence: 99%

Increased drug resistance is associated with reduced glucose levels and an enhanced glycolysis phenotype

Bhattacharya

Low

Soh

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSEThe testing of anticancer compounds in vitro is usually performed in hyperglycaemic cell cultures, although many tumours and their in vivo microenvironments are hypoglycaemic. Here, we have assessed, in cultures of tumour cells, the effects of reduced glucose levels on resistance to anticancer drugs and investigated the underlying cellular mechanisms. EXPERIMENTAL APPROACHPIK3CA mutant (AGS, HGC27), and wild-type (MKN45, NUGC4) gastric cancer cells were cultured in high-glucose (HG, 25 mM) or low-glucose (LG, 5 mM) media and tested for sensitivity to two cytotoxic compounds, 5-fluorouracil (5-FU) and carboplatin, the PI3K/mTOR inhibitor, PI103 and the mTOR inhibitor, Ku-0063794. KEY RESULTSAll cells had increased resistance to 5-FU and carboplatin when cultured in LG compared with HG conditions despite having similar growth and cell cycle characteristics. On treatment with PI103 or Ku-0063794, only the PIK3CA mutant cells displayed increased resistance in LG conditions. The PIK3CA mutant LG cells had selectively increased p-mTOR, p-S6, p-4EBP1, GLUT1 and lactate production, and reduced reactive oxygen species, consistent with increased glycolysis. Combination analysis indicated PI103 and Ku-0063794 were synergistic in PIK3CA mutant LG cells only. Synergism was accompanied by reduced mTOR signalling and increased autophagy. CONCLUSIONS AND IMPLICATIONSHypoglycaemia increased resistance to cytotoxic agents, especially in tumour cells with a high dependence on glycolysis. Dual inhibition of the PI3K/mTOR pathway may be able to attenuate such hypoglycaemia-associated resistance. Abbreviations

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“…Finally, it has been demonstrated in a preliminary report that mesangial mechano-growth factor (MGF), a splice variant of insulin-like growth factor-1 (IGF-1) involved in tissue repair and hypertrophy, is increased in glomeruli of diabetic mice and in nondiabetic GLUT1 - overexpressing transgenic mice [24], and is part of a GLUT1-MGF-positive feedback loop driving mesangial fibronectin synthesis [25]. In addition, recent data suggest a role for GLUT1-induced mTOR in mesangial dysfunction and glomerular disease in diabetes [26]. In experiments where GLUT1 was overexpressed in mesangial cells in the absence of high extracellular glucose, glucose flux and mTOR activity were increased.…”

Section: Facilitative Glucose Transport By Glut1 and Diabetic Nephropmentioning

confidence: 99%

“…In experiments where GLUT1 was overexpressed in mesangial cells in the absence of high extracellular glucose, glucose flux and mTOR activity were increased. Increased mTOR activity also leads to increased GLUT1 and glucose flux [26]. These data together suggested a feed-forward mechanism resulting in persistently increased GLUT1 and mTOR activity in diabetic glomeruli [26].…”

Section: Facilitative Glucose Transport By Glut1 and Diabetic Nephropmentioning

confidence: 99%

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GLUT1 Regulation of the Pro-Sclerotic Mediators of Diabetic Nephropathy

et al. 2013

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Diabetic glomerulosclerosis is characterized by accumulation of extracellular matrix proteins, mesangial expansion, and tubulointerstitial fibrosis. Hyperglycemia accelerates development of the disease, a direct result of increased intracellular glucose availability. The facilitative glucose transporter GLUT1 mediates mesangial cell glucose flux which leads to activation of signaling cascades favoring glomerulosclerosis, including pathways mediated by angiotensin II (Ang II), transforming growth factor β (TGF-β), connective tissue growth factor (CTGF), and vascular endothelial growth factor (VEGF). Ang II has both hemodynamic and metabolic effects directly inducing GLUT1 and/or matrix protein synthesis through diacyl glycerol (DAG) or protein kinase C (PKC) induction, mesangial cell stretch, and/or through transactivation of the epidermal growth factor receptor, the platelet-derived growth factor receptor, and the insulin-like growth factor-1 receptor, all of which may stimulate GLUT1 synthesis via an ERK-mediated pathway. Conversely, inhibition of Ang II effects suppresses GLUT1 and cellular glucose uptake. GLUT1-mediated glucose flux leads to metabolism of glucose via glycolysis, with induction of DAG, PKC, TGF-β₁, CTGF and VEGF. VEGF in turn triggers both GLUT1 and matrix synthesis. New roles for GLUT1-mTOR and GLUT1-mechano-growth factor interactions in diabetic glomerulosclerosis have also recently been suggested. Recent mouse models confirmed roles for GLUT1 in vivo in stimulating glomerular growth factor expression, growth factor receptors and development of glomerulosclerosis. GLUT1 may therefore act in concert with cytokines and growth factors to induce diabetic glomerulosclerosis. Further clarification of the pathways involved may prove useful for the therapy of diabetic nephropathy. New directions for investigation are discussed.

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GLUT1 enhances mTOR activity independently of TSC2 and AMPK

Abstract: Buller CL, Heilig CW, Brosius FC 3rd. GLUT1 enhances mTOR activity independently of TSC2 and AMPK.

Cited by 56 publications

References 42 publications

Functional Diversity

Functional Diversity

Increased drug resistance is associated with reduced glucose levels and an enhanced glycolysis phenotype

GLUT1 Regulation of the Pro-Sclerotic Mediators of Diabetic Nephropathy

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