Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.1.1 (hexokinase)
5,274 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have compared genomic DNA isolated from a series of rat hepatomas and from normal rat liver tissue by restriction fragment analysis. Our objective was to identify a tumor-specific restriction fragment that would be present in rapidly growing tumors and missing in normal tissues. Using a cDNA probe specific for the C-terminal half of rat brain hexokinase, we have identified several changes in DNA restriction fragment lengths in rat hepatomas vs. normal rat liver. Most of these involved restriction fragments that were present in normal rat DNA and missing in tumor DNA. However, one HinfI fragment of M(r) = 13.4 kilobase pairs (kb) was found to be present in rapidly growing rat hepatomas, but missing in normal rat tissue and in hepatomas of slow or intermediate growth rate.
Int J Cancer 1993 Feb 20
PMID:Detection of a progression-linked DNA restriction fragment in rat hepatoma cells probed with a hexokinase cDNA. 809 14

The purpose of this study was to evaluate some indicators of the pathogenesis of cancer cachexia in which the growth of the CaNT tumor markedly alters the metabolism and induces measurable biochemical changes of the host. An increase of hexokinase and lactate dehydrogenase activities with tumor volume, coupled with the decline of oxygen consumption are shown in this work. Furthermore changes in the mean spin lattice and spin-spin relaxation time values of the tumor provide additional information of the abnormal cellular spatial and metabolic relationships that exists within the tumor. In the liver of the host, the augmentation of the oxygen uptake and specific activities of lactate dehydrogenase and fructose-1,6-diphosphatase shown in this work, reflecting an increase in the glucose metabolism rate and thus, energy expenditure of the host. This may envisage some correlation with the onset of biochemical changes in the homeostatic derangement in the host during the fast growth of the tumor.
Cancer Biochem Biophys 1993 Sep
PMID:Homeostatic derangement in the CBA rodent host during the growth of the CaNT tumor. 852 75

The increased glucose consumption of many tumor cells depends to a large extent on the overexpression of hexokinase Type II. In a previous study we isolated and sequenced the hepatoma Type II hexokinase promoter and showed that it is activated by glucose in the highly glycolytic AS-30D hepatoma cell line under study, but not activated in control hepatocytes [Mathupala, S.P., Rempel, A. and Pedersen, P.L. (1995) J. Biol. Chem. 270, 16918-16925]. Here we report that the promoter of the hexokinase Type II gene is maximally activated by glucose at concentrations above 5 mM. Moreover, the data strongly suggest that glucose can act alone without requirement for metabolism. Also, glucose-mediated promoter activation is markedly potentiated by cAMP. This response may serve as a strategy for cancer cells to maintain the hexokinase transcription rate high to ensure an efficient glucose utilization even under conditions where carbohydrates are limiting.
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PMID:Glucose catabolism in cancer cells: regulation of the Type II hexokinase promoter by glucose and cyclic AMP. 864 58

Hexokinase type II is highly overexpressed in many cancer cells, where it plays a pivotal role in the high glycolytic phenotype. Here we demonstrate by Southern blot analysis and fluorescence in situ hybridization (FISH) that in the rapidly growing rat AS-30D hepatoma cell line, enhanced hexokinase activity is associated with at least a 5-fold amplification of the type II gene relative to normal hepatocytes. This amplification is located chromosomally, extends to the whole gene, and most likely occurs at the site of the resident gene. No rearrangement of the gene could be detected. Therefore, overexpression of hexokinase type II in AS-30D hepatoma cells may be based, at least in part, on a stable gene amplification. This is the first report describing the amplification of a hexokinase gene in a tumor cell line expressing the high glycolytic phenotype.
Cancer Res 1996 Jun 01
PMID:Glucose catabolism in cancer cells: amplification of the gene encoding type II hexokinase. 865 77

The development of new diagnostic/therapeutic modalities for cancer requires a specific understanding of how tumors differ from normal tissues. Though the key components involved in the selective accumulation of 2-deoxy-D-glucose (2-DG) analogs in tumors are known, the relative importance of each is controversial. For this reason glucose transport protein (GLUT) density, hexokinase/glucose-6-phosphatase (GP) activity, and 2-DG biodistribution were measured together in four tumor models and normal murine tissues. Direct binding studies with 3H-cytochalasin B showed that GLUT density was elevated 20-fold in LX-1 tumors. Immunohistochemically in all tumors, the expression of GLUT-1 was highest in the necrotic/ perinecrotic foci and similar in cells not adjacent to necrotic foci. As the retention of 3H-2-DG was similar in all tumors, these data suggest that the GLUT-1 in perinecrotic tumor cells were not rate limiting for 3H-2-DG uptake. Kidney, liver, and lung had high GP activity and rapid clearance of 3H-2-DG. Sodium orthovanadate (5 mumol), a GP inhibitor, increased the concentration of 3H-2-DG in these tissues, suggesting that GP is a rate-limiting enzyme for 3H-2-DG clearance. All tumor homogenates had low GP activity, and hexokinase activity was not elevated compared to normal tissues. Thus, in the tumors studied, the selective accumulation of 3H-2-DG consistently occurred in the absence of significant GP activity without the marked overexpression of hexokinase or GLUT.
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PMID:The interaction among glucose transport, hexokinase, and glucose-6-phosphatase with respect to 3H-2-deoxyglucose retention in murine tumor models. 883 12

Increased glycolysis is a characteristic of cancer cells. Though less efficient in energy production, it ensures continuous supply of energy and phosphometabolites for biosynthesis enabling metastatic and less vascularized cancer cells to proliferate even under hypoxic conditions. Since hexokinase is the first rate limiting enzyme in the glycolytic pathway, elevated levels of Type II like hexokinase in tumors are of great significance in this context. Under normal conditions insulin regulates expression of hexokinase Type II isoenzyme, which is predominantly expressed in muscle. On the other hand cancer cells overexpress insulin-like growth factors and their receptors which mimic many activities of insulin. This prompted us to examine a hypothesis that insulin-like growth factors may be responsible for overexpression of tumor hexokinase. Our experiments demonstrate that insulin-like growth factor I indeed induces hexokinase gene expression in a concentration and time dependent manner in two cancer cell lines we studied.
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PMID:Insulin-like growth factor I induces tumor hexokinase RNA expression in cancer cells. 919 3

Twenty-six different hepatoma cell lines established from cancer-prone transgenic mice exhibited a close correlation between expression of the GLUT 2 glucose transporter and activation of the L-type pyruvate kinase (L-PK) gene by glucose, as judged by Northern blot analyses and transient transfection assays. The L-PK gene and a transfected L-PK construct were silent in GLUT 2(+) cells and active in GLUT 2(-) cells cultured in glucose-free medium. Transfection of GLUT 2(-) cells with a GLUT 2 expression vector restored the inducibility of the L-PK promoter by glucose, mainly by suppressing the glucose-independent activity of this promoter. Culture of GLUT 2(-) cells, in which the L-PK gene is constitutively expressed, in a culture medium using fructose as fuel selected GLUT 2(+) clones in which the L-PK gene responded to glucose. The expression of the L-PK gene in GLUT 2(-) cells cultured in the absence of glucose was correlated with a high intracellular glucose 6-phosphate (Glu-6-P) concentration while under similar culture conditions Glu-6-P concentration was very low in GLUT 2(+) cells. Consequently, a role of GLUT 2 in the glucose responsiveness of glucose-sensitive genes in cultured hepatoma cells could be to allow for Glu-6-P depletion under gluconeogenic culture conditions. In the absence of GLUT 2, glucose endogeneously produced might be unable to be exported from the cells and would be phosphorylated again to Glu-6-P by constitutively expressed hexokinase isoforms, continuously generating the glycolytic intermediates active on the L-PK gene transcription.
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PMID:Role of the GLUT 2 glucose transporter in the response of the L-type pyruvate kinase gene to glucose in liver-derived cells. 921 18

The p53 tumor suppressor is found to be mutated and abundant in a wide variety of tumors. Within tumors showing rapid growth, the Type II isoform of hexokinase is also highly expressed to facilitate high rates of glucose catabolism, which in turn promote their rapid proliferation. We previously reported isolation of the proximal promoter of the Type II hexokinase gene from the highly glycolytic hepatoma AS-30D (Mathupala, S. P., Rempel, A., and Pedersen, P. L. (1995) J. Biol. Chem. 270, 16918-16925). Here, we show that a p53 protein, exhibiting two point mutations in its cDNA, is abundantly expressed in the AS-30D hepatoma. Co-expression studies showed that p53 overexpression significantly and reproducibly activated the Type II hexokinase promoter. Two functional p53 motifs were identified within this promoter by footprint and gel retardation analyses. Presence of functional p53 response elements on the Type II hexokinase promoter and the positive regulatory effect on the promoter by the mutant p53 indicates that in rapidly growing liver tumors, and perhaps in many other tumors as well, this highly abundant p53 protein plays a role in maintaining a high glycolytic rate. This is the first report of a possible link between loss of cell cycle control in rapidly growing cancer cells and their high glycolytic phenotype.
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PMID:Glucose catabolism in cancer cells. The type II hexokinase promoter contains functionally active response elements for the tumor suppressor p53. 927 38

For more than two-thirds of this century we have known that one of the most common and profound phenotypes of cancer cells is their propensity to utilize and catabolize glucose at high rates. This common biochemical signature of many cancers, particularly those that are poorly differentiated and proliferate rapidly, has remained until recently a "metabolic enigma." However, with many advances in the biological sciences having been applied to this problem, cancer cells have begun to reveal their molecular strategies in maintaining an aberrant metabolic behavior. Specifically, studies performed over the past two decades in our laboratory demonstrate that hexokinase, particularly the Type II isoform, plays a critical role in initiating and maintaining the high glucose catabolic rates of rapidly growing tumors. This enzyme converts the incoming glucose to glucose-6-phosphate, the initial phosphorylated intermediate of the glycolytic pathway and an important precursor of many cellular "building blocks." At the genetic level the tumor cell adapts metabolically by first increasing the gene copy number of Type II hexokinase. The enzyme's gene promoter, in turn, shows a wide promiscuity toward the signal transduction cascades active within tumor cells. It is activated by glucose, insulin, low oxygen "hypoxic" conditions, and phorbol esters, all of which enhance the rate of transcription. Also, the tumor cell uses the tumor suppressor p53, which is usually modified by mutations to debilitate cell cycle controls, to further activate hexokinase gene transcription. This results in both enhanced levels of the enzyme, which binds to mitochondrial porins thus gaining preferential access to mitochondrially generated ATP, and in a decreased susceptibility to product inhibition and proteolytic degradation. Significantly, these multiple strategies all work together to enable tumor cells to develop a metabolic strategy compatible with rapid proliferation and prolonged survival.
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PMID:Aberrant glycolytic metabolism of cancer cells: a remarkable coordination of genetic, transcriptional, post-translational, and mutational events that lead to a critical role for type II hexokinase. 938 94

Current thought is that proliferating cells undergo a shift from oxidative to glycolytic metabolism, where the energy requirements of the rapidly dividing cell are provided by ATP from glycolysis. Drawing on the hexokinase-mitochondrial acceptor theory of insulin action, this article presents evidence suggesting that the increased binding of hexokinase to porin on mitochondria of cancer cells not only accelerates glycolysis by providing hexokinase with better access to ATP, but also stimulates the TCA cycle by providing the mitochondrion with ADP that acts as an acceptor for phosphoryl groups. Furthermore, this acceleration of the TCA cycle stimulates protein synthesis via two mechanisms: first, by increasing ATP production, and second, by provision of certain amino acids required for protein synthesis, since the amino acids glutamate, alanine, and aspartate are either reduction products or partially oxidized products of the intermediates of glycolysis and the TCA cycle. The utilization of oxygen in the course of the TCA cycle turnover is relatively diminished even though TCA cycle intermediates are being consumed. With partial oxidation of TCA cycle intermediates into amino acids, there is necessarily a reduction in formation of CO2 from pyruvate, seen as a relative diminution in utilization of oxygen in relation to carbon utilization. This has been assumed to be an inhibition of oxygen uptake and therefore a diminution of TCA cycle activity. Therefore a switch from oxidative metabolism to glycolytic metabolism has been assumed (the Crabtree effect). By stimulating both ATP production and protein synthesis for the rapidly dividing cell, the binding of hexokinase to mitochondrial porin lies at the core of proliferative energy metabolism. This article further reviews literature on the binding of the isozymes of hexokinase to porin, and on the evolution of insulin, proposing that intracellular insulin-like proteins directly bind hexokinase to mitochondrial porin.
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PMID:Hexokinase binding to mitochondria: a basis for proliferative energy metabolism. 938 93


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