Alterations in Glucose Metabolism in Chick-Embryo Cells Transformed by Rous Sarcoma Virus: Intracellular Levels of Glycolytic Intermediates

Singh, Vir; Singh, Mongjam Meghachandra; August, J. T.; Horecker, B.L.

doi:10.1073/pnas.71.10.4129

Cited by 87 publications

(28 citation statements)

References 41 publications

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“…In glycolysis, the most fully studied of the pathways, the transphosphorylation reactions are precisely the ones that regulate the flow of glucose to pyruvate (10). They have been shown to be activated by serum (6) and by virus-induced transformation (11). It has been shown that limiting the external supply of Mg2+ causes reductions in the rates of DNA, RNA, and protein synthesis, glycolysis, and the transport of 2-deoxy-D-glucose, reductions similar to those observed after removing serum or increasing population density (12).…”

mentioning

confidence: 54%

Mutual potentiation by magnesium and calcium of growth in animal cells.

Rubin¹,

Koide²

1976

Proc. Natl. Acad. Sci. U.S.A.

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The effects on DNA synthesis of various combinations of Mg2+ and Ca2+ in cultures of chick embryo cells have been studied. When [Mg2+1 2 0.24 mM, reduction of Ca2+ from the standard concentration of 1.72 mM to 0.01 mM had no effect on the incorporation of [3H~thymidine ([3H] The rate of progress of cultured mouse thymocytes into the S-period of the cell cycle is dependent on the concentration of Ca2+ in the medium (1). Chick embryo fibroblasts (CEF) also require Ca2+ to maintain high rates of DNA synthesis, but in amounts so small that a chelating agent has to be used to eliminate contaminating traces of the cation before inhibitory effects can be detected (2). CEF transformed by infection with Rous sarcoma virus are reported to be unaffected by the removal of Ca2 , and this has been interpreted to mean that Ca2+ is not an essential requirement for the initiation of DNA synthesis, but that it plays a regulatory role in nontransformed cells (2). In support of this thesis is the recent finding that DNA synthesis in quiescent 3T3 cultures can be stimulated by adding Ca2+ in great excess over the physiological concentration (3).The investigations of the regulatory role of Ca2+ have been restricted to measurements of DNA synthesis, mitosis, and cell number. However, factors such as serum concentration, pH, and population density, which regulate cell proliferation, also regulate, coordinately, many independent metabolic pathways (4). In fibroblasts these include the metabolism of hexoses (5, 6), RNA and protein synthesis (7), and the execution of the differentiated fibroblast functions of hyaluronic acid (8) and collagen production (9). Ca2+ is not known to play a significant role in these metabolic pathways (10), and any involvement it may have in their coordinate control is probably indirect.Mg2+ is directly involved in all the regulated metabolic pathways, since it is required for the crucial transphosphorylation reactions (10). In glycolysis, the most fully studied of the pathways, the transphosphorylation reactions are precisely the ones that regulate the flow of glucose to pyruvate (10). They have been shown to be activated by serum (6) and by virus-induced transformation (11). It has been shown that limiting the external supply of Mg2+ causes reductions in the rates of DNA, RNA, and protein synthesis, glycolysis, and the transport of 2-deoxy-D-glucose, reductions similar to those observed after removing serum or increasing population density (12). The intracellular availability of free Mg2+ has been proposed as the central factor in the coordinate control of metabolism and growth in animal cells (12), with the effects produced by varying the external [Ca2+] possibly arising from the relation between [Ca2+] and the availability of free Mg2+ within the cell.We now report an investigation of the related effects of Mg2+ and Ca2+ on CEF. We find that reduction of [Ca2+] from the medium to the 0.01-0.02 mM Ca2+ that occurs as a contaminant of the other ingredients of the growth medium, has no effect on DNA...

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mentioning

confidence: 54%

Mutual potentiation by magnesium and calcium of growth in animal cells.

Rubin¹,

Koide²

1976

Proc. Natl. Acad. Sci. U.S.A.

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“…Multifactorial processes are suggested to regulate pat- terned death of PCs, including energy failure, glutamate toxicity, climbing fiber-mediated excitotoxicity, and exclusive expression of other host proteins in PC subsets (e.g., p75, the low-affinity nerve growth factor receptor) (15,24,42,69,70,71,74,76). Viral transformation and viral infection can cause metabolic changes in infected cells, resulting in enhanced glucose uptake and glycolytic flux and in depletion of intracellular ATP (5,6,19,26,63,67). Decreased ATP levels may reflect a consumptive necessity in infected cells for efficient viral replication (i.e., viral DNA/RNA and polypeptide synthesis).…”

Section: Discussionmentioning

confidence: 99%

Spatiotemporal Analysis of Purkinje Cell Degeneration Relative to Parasagittal Expression Domains in a Model of Neonatal Viral Infection

Williams

Yaddanapudi

Hornig

et al. 2007

J Virol

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Infection of newborn Lewis rats with Borna disease virus (neonatal Borna disease [NBD]) results in cerebellar damage without the cellular inflammation associated with infections in later life. Purkinje cell (PC) damage has been reported for several models of early-life viral infection, including NBD; however, the time course and distribution of PC pathology have not been investigated rigorously. This study examined the spatiotemporal relationship between PC death and zonal organization in NBD cerebella. Real-time PCR at postnatal day 28 (PND28) revealed decreased cerebellar levels of mRNAs encoding the glycolytic enzymes aldolase C (AldoC, also known as zebrin II) and phosphofructokinase C and the excitatory amino acid transporter 4 (EAAT4). Zebrin II and EAAT4 immunofluorescence analysis in PND21, PND28, PND42, and PND84 NBD rat cerebella revealed a complex pattern of PC degeneration. Early cell loss (PND28) was characterized by preferential apoptotic loss of zebrin II/EAAT4-negative PC subsets in the anterior vermis. Consistent with early preferential loss of zebrin II/EAAT4-negative PCs in the vermis, the densities of microglia and the Bergmann glial expression of metallothionein I/II and the hyaluronan receptor CD44 were higher in zebrin II/EAAT4-negative zones. In contrast, early loss in lateral cerebellar lobules did not reflect a similar discrimination between PC phenotypes. Patterns of vermal PC loss became more heterogeneous at PND42, with the loss of both zebrin II/EAAT4-negative and zebrin II/EAAT4-positive neurons. At PND84, zebrin II/EAAT4 patterning was abolished in the anterior cerebellum, with preferential PC survival in lobule X. Our investigation reveals regional discrimination between patterns of PC subset loss, defined by zebrin II/EAAT4 expression domains, following neonatal viral infection. These findings suggest a differential vulnerability of PC subsets during the early stages of virus-induced neurodegeneration.

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“…mTOR has also been reported to stimulate HIF-1α stabilization and transactivation domain function (81). Studies of the Rous sarcoma virus (RSV) four decades ago revealed that one of the earliest changes in the phenotype of RSV-infected cells was an increased rate of glycolysis that was dependent upon the activity of the V-SRC oncoprotein (82)(83)(84), and V-SRC was the first oncogene shown to induce HIF-1 transcriptional activity, leading to increased expression of genes encoding glycolytic enzymes under nonhypoxic conditions (85).…”

Section: Cancer-associated Mutations Alter Metabolism In An Hifdependmentioning

confidence: 99%

HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations

Semenza¹

2013

J. Clin. Invest.

1,106

999

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Hypoxia occurs frequently in human cancers and induces adaptive changes in cell metabolism that include a switch from oxidative phosphorylation to glycolysis, increased glycogen synthesis, and a switch from glucose to glutamine as the major substrate for fatty acid synthesis. This broad metabolic reprogramming is coordinated at the transcriptional level by HIF-1, which functions as a master regulator to balance oxygen supply and demand. HIF-1 is also activated in cancer cells by tumor suppressor (e.g., VHL) loss of function and oncogene gain of function (leading to PI3K/AKT/mTOR activity) and mediates metabolic alterations that drive cancer progression and resistance to therapy. Inhibitors of HIF-1 or metabolic enzymes may impair the metabolic flexibility of cancer cells and make them more sensitive to anticancer drugs. IntroductionAll human cells require a constant supply of O 2 to carry out oxidative phosphorylation in the mitochondria for ATP generation. Under hypoxic conditions when O 2 availability is reduced, cells generally respond in three ways: (a) cell proliferation is inhibited to prevent any further increase in the number of O 2 -consuming cells; (b) the rate of oxidative phosphorylation is decreased and the rate of glycolysis is increased in order to decrease O 2 consumption per cell; and (c) the production of angiogenic factors is increased in order to increase O 2 delivery. Mutations in cancer cells dysregulate cell growth and metabolism, but the mechanisms and consequences of this dysregulation vary widely from one cancer to another and even one from cancer cell to another. In some cancer cells, O 2 still regulates the rate of cell proliferation, whereas others continue to divide even under severely hypoxic conditions; some cancers are well vascularized and perfused, whereas most cancers contain steep O 2 gradients that reflect the distance to the nearest blood vessel, the number of intervening cells and their metabolic activity, and the rate at which blood is flowing through the vessel. The metabolism of individual cancer cells reflects the presence of particular genetic alterations, which may alter metabolism in an O 2 -independent manner, as well as the spatial and temporal heterogeneity of O 2 availability within the tumor microenvironment. This Review summarizes the role of HIF-1 in the regulation of cancer cell metabolism, focusing primarily on the use of glucose as a metabolic substrate.

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Alterations in Glucose Metabolism in Chick-Embryo Cells Transformed by Rous Sarcoma Virus: Intracellular Levels of Glycolytic Intermediates

Cited by 87 publications

References 41 publications

Mutual potentiation by magnesium and calcium of growth in animal cells.

Mutual potentiation by magnesium and calcium of growth in animal cells.

Spatiotemporal Analysis of Purkinje Cell Degeneration Relative to Parasagittal Expression Domains in a Model of Neonatal Viral Infection

HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations

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