Early effects of phytohaemagglutinin on glucose metabolism of normal human lymphocytes

Hedeskov, C. J.

doi:10.1042/bj1100373

Cited by 106 publications

(66 citation statements)

References 25 publications

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“…For rat T lymphocytes stimulated with lectins and interleukins, activation results in a 53-fold increase in glucose metabolism. [159][160][161][162][163] The activity of individual glycolytic enzymes increased 12-to 30-fold upon stimulation. Increasing the dose of IL-3 administered to FL5.12 cells results in an 8-fold increase in glycolytic flux.…”

Section: Quiescence In Lymphocytesmentioning

confidence: 99%

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et al. 2012

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Ensuring the continuity of life requires that individual cells and entire organisms can survive not only in ideal environments, but also in conditions of scarcity. When conditions are unfavorable for proliferation, many cells have the capacity to enter a nondividing state, sometimes for years, while retaining their ability to reenter the proliferative cell cycle. 1,2 This state of reversible cell cycle arrest, known as quiescence, is common and can be seen in stem cells, eggs and spores. Some quiescent cells are surprisingly hardy: they can survive long periods of nutrient starvation, cold temperatures and even desiccation. Entry into quiescence is often associated with dramatic changes in metabolism, defined as the uptake of nutrients and the use of these nutrients for the synthesis of macromolecules and energy. Indeed, proliferating and quiescent fibroblasts are expected to have very different metabolic requirements. While proliferating cells must devote much of their metabolic capacity to biosynthesis in order to create the material necessary to form a new cell, quiescent cells are relieved of this steep metabolic requirement. Many but not all quiescent cells respond by downregulating the synthesis of proteins *Correspondence to: Hilary Coller; Email: hcoller@princeton.edu Submitted: 02/22/12; Accepted: 02/27/12 http://dx.doi.org/10. 4161/cc.19879 Quiescence is a state of reversible cell cycle arrest that can grant protection against many environmental insults. in some systems, cellular quiescence is associated with a low metabolic state characterized by a decrease in glucose uptake and glycolysis, reduced translation rates and activation of autophagy as a means to provide nutrients for survival. For cells in multiple different quiescence model systems, including Saccharomyces cerevisiae, mammalian lymphocytes and hematopoietic stem cells, the Pi3Kinase/TOr signaling pathway helps to integrate information about nutrient availability with cell growth rates. Quiescence signals often inactivate the TOr kinase, resulting in reduced cell growth and biosynthesis. However, quiescence is not always associated with reduced metabolism; it is also possible to achieve a state of cellular quiescence in which glucose uptake, glycolysis and flux through central carbon metabolism are not reduced. in this review, we compare and contrast the metabolic changes that occur with quiescence in different model systems. 2 The signals for quiescence vary for different types of cells. Bacteria and yeast can enter stationary phase, a condition in which they cease cell growth and proliferation, in response to depletion of the glucose in their culture medium or in response to deprivation for a specific nutrient. In mammals, the proliferative state of individual cells is regulated by a host of factors that include not only the presence or absence of nutrients, but also cues from proliferative signaling molecules such as mitogens and situational cues. Quiescent T lymphocytes respond to stimulation of their T-cell receptor with the approp...

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Section: Quiescence In Lymphocytesmentioning

confidence: 99%

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et al. 2012

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“…Growth factor stimulated cell growth and proliferation result in the consumption of energy and macromolecular precursors, which might therefore stimulate glycolysis as a cellintrinsic response to a decline in an intracellular metabolic indicator such as ATP/ADP ratio, NADH/NAD + ratio, or mitochondrial membrane potential (3,5). Bioenergetic demand can stimulate compensatory increases in glucose metabolism in specific settings.…”

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Cytokine stimulation of aerobic glycolysis in hematopoietic cells exceeds proliferative demand

et al. 2004

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The relationship between growth factor-dependent cell growth and proliferation and the upregulation of cellular metabolism required to support these processes remains poorly defined. Here, we demonstrate that cell growth, proliferation, and glucose metabolism are coordinately regulated by interleukin-3 (IL-3) in cytokine-dependent cells. Surprisingly, glycolytic activity is stimulated to a greater extent than would be expected based on the rate of cell growth or proliferation. IL-3 signaling exerts a direct effect on glycolytic commitment independent of cell growth control. These results are not restricted to IL-3 as the cytokines IL-7 and IL-2 have similar effects on glucose metabolism when assayed in factor-dependent cell lines or primary lymphocytes, respectively. Growth factor stimulation leads cells to consume less oxygen and produce more lactate per glucose, indicative of conversion from oxidative to glycolytic metabolism. The enforced rate of glucose metabolism is in excess of that required to support cell growth; accordingly, if extracellular glucose is reduced, cells retain the ability to grow and proliferate by derepressing oxidative metabolism. These data suggest that the high rate of glycolysis observed in response to growth factor stimulation is a primary effect rather than a homeostatic response to increased cell growth.Keywords growth factor; interleukin-3; glucose metabolism; cell sizeThe growth, proliferation, and survival of cells within multicellular organisms depend on the presence of appropriate extracellular signals (1). These cues maintain the delicate balance between cell accumulation and cell death necessary for normal development and tissue homeostasis. These signals can arise from cellular interactions with soluble proteins such as cytokines, with other cells, or with the extracellular matrix. Extracellular signals that promote cell growth also result in increased glucose utilization. For example, early studies demonstrated that lectin stimulation of lymphocytes increased their glucose uptake, rate of glycolysis, and pentose phosphate shunt activity (2-4). Growth factor stimulated cell growth and proliferation result in the consumption of energy and macromolecular precursors, which might therefore stimulate glycolysis as a cellintrinsic response to a decline in an intracellular metabolic indicator such as ATP/ADP ratio, NADH/NAD + ratio, or mitochondrial membrane potential (3, 5). Bioenergetic demand can stimulate compensatory increases in glucose metabolism in specific settings. For instance, glycolytic rates rise in cells in which ATP consumption is increased or in which respiration is impaired (6-10). However, recent studies in our laboratory have indicated that growth factor signals serve to maintain levels of intracellular bioenergetic indicators such as ATP/ ADP, NADH/NAD + , and mitochondrial membrane potential (11,12). This suggested that receptors that promote cell growth might directly regulate the cellular uptake and utilization of essential nutrients, such as gluco...

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“…1 Supported by National Institutes of Health training grants. 2 Supported by a Leukemia and Lymphoma Society Fellowship Award. 3 ␤-oxidation, which produces substrates that maintain ATP generation through oxidative phosphorylation.…”

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confidence: 99%

“…These signals, which include cytokines and other lineage-specific growth factors, stimulate signal transduction pathways that orchestrate cellular metabolism through effects on gene expression and enzyme kinetics. Together, these signal-induced changes function to direct uptake and utilization of nutrients, channeling metabolites into biosynthetic pathways (2)(3)(4). One important example of this phenomenon occurs during lymphocyte stimulation, where receptor-induced signaling directly increases glucose transport, glycolysis, lactate production, and synthesis of lipids (5)(6)(7)(8)(9).…”

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confidence: 99%

Phosphatidylinositol 3-Kinase-dependent Modulation of Carnitine Palmitoyltransferase 1A Expression Regulates Lipid Metabolism during Hematopoietic Cell Growth

DeBerardinis

Lum

Thompson

2006

Journal of Biological Chemistry

201

163

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An abundant supply of extracellular nutrients is believed to be sufficient to suppress catabolism of cellular macromolecules. Here we show that, despite abundant extracellular nutrients, interleukin-3-deprived hematopoietic cells begin to catabolize intracellular lipids. Constitutive Akt activation blunts the increased ␤-oxidation that accompanies growth factor withdrawal, and in growth factor-replete cells, phosphatidylinositol 3-kinase (PI3K) signaling is required to suppress lipid catabolism. Surprisingly, PI3K and Akt exert these effects by suppressing expression of the ␤-oxidation enzyme carnitine palmitoyltransferase 1A (CPT1A). Cells expressing a short hairpin RNA against CPT1A fail to induce ␤-oxidation in response to growth factor withdrawal and are unable to survive glucose deprivation. When CPT1A is constitutively expressed, growth factor stimulation fails to repress ␤-oxidation. As a result, both net lipid synthesis and cell proliferation are diminished. Together, these results demonstrate that modulation of CPT1A expression by PI3K-dependent signaling is the major mechanism by which cells suppress ␤-oxidation during anabolic growth.Single-cell eukaryotes like yeast autonomously regulate their uptake of nutrients from the extracellular environment. In such organisms, cellular metabolism is regulated primarily in response to nutrient availability (1). In contrast, it has been proposed that mammalian cells do not take up and metabolize nutrients without instruction from extracellular signals. These signals, which include cytokines and other lineage-specific growth factors, stimulate signal transduction pathways that orchestrate cellular metabolism through effects on gene expression and enzyme kinetics. Together, these signal-induced changes function to direct uptake and utilization of nutrients, channeling metabolites into biosynthetic pathways (2-4). One important example of this phenomenon occurs during lymphocyte stimulation, where receptor-induced signaling directly increases glucose transport, glycolysis, lactate production, and synthesis of lipids (5-9).Many of the metabolic changes elicited by growth factors result from activation of the phosphatidylinositol 3-kinase (PI3K)/Akt 4 signaling system. In this pathway, binding of a growth factor to its surface receptor induces activation of the lipid kinase PI3K, which phosphorylates phosphatidylinositol species (10). End products of PI3K activity recruit the serine/ threonine kinase Akt to the plasma membrane where it becomes a substrate for phosphorylation and activation by phosphoinositide-dependent protein kinase 1 and other regulatory kinases (10). The metabolic effects of growth factorinduced PI3K/Akt stimulation include increases in glucose import and glycolysis, which fuel the bioenergetic and biosynthetic activities of growing cells (11-13). Constitutive activation of PI3K and/or Akt through a variety of genetic mechanisms is a common transforming event in human cancer, including some 25% of breast carcinoma and 30% of colon carcinoma (14 -1...

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Early effects of phytohaemagglutinin on glucose metabolism of normal human lymphocytes

Cited by 106 publications

References 25 publications

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Cytokine stimulation of aerobic glycolysis in hematopoietic cells exceeds proliferative demand

Phosphatidylinositol 3-Kinase-dependent Modulation of Carnitine Palmitoyltransferase 1A Expression Regulates Lipid Metabolism during Hematopoietic Cell Growth

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