Studies on the mechanism by which glutamine and heat shock increase lactate synthesis by l929 cells in the presence of insulin

Lanks, Karl W.

doi:10.1002/jcp.1041290317

Cited by 5 publications

(2 citation statements)

References 17 publications

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“…The major fate of glutamine carbon in the mitochondria in mammalian cultured cells is to enter the tricarboxylic acid cycle for partial or complete oxidation to C02 (Tildon and Zielke, 1988). The production of C02 from glutamine increases in Kc cells in heat shock conditions consistent with an earlier report on L929 cells (Lanks, 1986b), and ammonia production from glutamine dramatically increases (Sanders and Kon, manuscript in preparation). These findings are also consistent with early indications of mitochondria1 involvement in regulation of heat shock expression (Ritossa, 1962;Leenders and Berendes, 1972).…”

Section: Discussionsupporting

confidence: 89%

Glutamine is a powerful effector of heat shock protein expression in Drosophila Kc cells

Sanders¹,

Kon²

1991

Journal Cellular Physiology

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We have investigated the effects of extracellular anions on the regulation of expression of the heat shock response in Drosophila Kc cells incubated in defined balanced salt solutions. Widely varying chloride concentrations had no effect on normal or heat shock protein (hsp) expression. Increasing glutamate concentrations from zero to 15 mM increased hsp expression more than 100-fold while affecting expression of non-heat-shock proteins minimally. Glutamine was 20-100-fold more potent than glutamate in supporting hsp expression, while other amino acids were less effective or supported no detectable hsp synthesis in heat shock. Inhibition of glutamine synthetase with methionine-sulfoximine resulted in very low hsp expression with glutamate and normal high level expression with glutamine, confirming the importance of glutamine. The absence of glucose and treatment with 2-deoxyglucose did not change the requirement for adequate glutamine for hsp expression. Cells heat shocked under conditions which gave very low hsp expression resumed growth when returned to normal medium as well as cells which expressed normal levels of hsps. Measurements of free amino acid levels in cells heat shocked in the presence and absence of glutamine showed a correlation between glutamine levels and amount of hsp expression. We conclude that a physiological process regulated by glutamine or a glutamine metabolite is important for normal hsp expression in heat shock conditions in Drosophila.

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Section: Discussionsupporting

confidence: 89%

Glutamine is a powerful effector of heat shock protein expression in Drosophila Kc cells

Sanders¹,

Kon²

1991

Journal Cellular Physiology

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“…Nutritional deprivation inhibits mTORC1 and promotes autophagy [15], [16]. It may be significant that HSF1 requires glutamine for activity (essential for mTORC1), promotes translation, one of the earliest findings in study of HSP expression [19]–[20]. HSF1−/− cells are significantly reduced in size, consistent with a role for HSF1 in cell size and perhaps mTORC1 function [21], [22].…”

Section: Introductionmentioning

confidence: 85%

mTOR Is Essential for the Proteotoxic Stress Response, HSF1 Activation and Heat Shock Protein Synthesis

et al. 2012

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The target of rapamycin (TOR) is a high molecular weight protein kinase that regulates many processes in cells in response to mitogens and variations in nutrient availability. Here we have shown that mTOR in human tissue culture cells plays a key role in responses to proteotoxic stress and that reduction in mTOR levels by RNA interference leads to increase sensitivity to heat shock. This effect was accompanied by a drastic reduction in ability to synthesize heat shock proteins (HSP), including Hsp70, Hsp90 and Hsp110. As HSP transcription is regulated by heat shock transcription factor 1 (HSF1), we examined whether mTOR could directly phosphorylate this factor. Indeed, we determined that mTOR could directly phosphorylate HSF1 on serine 326, a key residue in transcriptional activation. HSF1 was phosphorylated on S326 immediately after heat shock and was triggered by other cell stressors including proteasome inhibitors and sodium arsenite. Null mutation of S326 to alanine led to loss of ability to activate an HSF1-regulated promoter-reporter construct, indicating a direct role for mTOR and S326 in transcriptional regulation of HSP genes during stress. As mTOR is known to exist in at least two intracellular complexes, mTORC1 and mTOR2 we examined which complex might interact with HSF1. Indeed mTORC1 inhibitor rapamycin prevented HSF1-S326 phosphorylation, suggesting that this complex is involved in HSF1 regulation in stress. Our experiments therefore suggest a key role for mTORC1 in transcriptional responses to proteotoxic stress.

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The role of reduced nicotinamide adenine dinucleotide phosphate in glucose- and temperature-dependent doxorubicin cytotoxicity

Gao

Friedman

Lanks

1993

Cancer Chemother. Pharmacol.

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The mechanism of doxorubicin resistance induced by glucose deprivation was examined using an L929 cell system. Resistance developed even when the synthesis of glucose-regulated proteins was suppressed by supplementing glucose-deprived cultures with uridine. Resistance was also not correlated with pyruvate availability, with DNA strand breaks, or with intracellular drug or nucleotide levels. However, intracellular concentrations of reduced nicotinamide adenine dinucleotide phosphate (NADPH) decreased to undetectable levels in glucose-deprived cells with or without uridine supplementation. NADPH depletion induced by treating glucose-fed cells with low concentrations of methylene blue afforded the same degree of protection as glucose deprivation, and normal sensitivity could be restored to glucose-deprived cells by adding NADPH to the culture medium. These results suggest that decreased NADPH availability is responsible for the doxorubicin resistance induced by glucose deprivation. Although drug uptake and NADPH production increased with temperature, these effects could not fully account for the > 1000-fold decrease in clonogenic survival observed over the 25 degrees-37 degrees C temperature range. Similarly, manipulation of NADPH levels confirmed a role for drug bioreduction in the cytotoxic mechanism but did not suggest that NADPH availability was rate-limiting for this process at any temperature employed.

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Studies on the mechanism by which glutamine and heat shock increase lactate synthesis by l929 cells in the presence of insulin

Cited by 5 publications

References 17 publications

Glutamine is a powerful effector of heat shock protein expression in Drosophila Kc cells

Glutamine is a powerful effector of heat shock protein expression in Drosophila Kc cells

mTOR Is Essential for the Proteotoxic Stress Response, HSF1 Activation and Heat Shock Protein Synthesis

The role of reduced nicotinamide adenine dinucleotide phosphate in glucose- and temperature-dependent doxorubicin cytotoxicity

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