TY - JOUR
T1 - Glucose catabolism in cancer cells
T2 - Identification and characterization of a marked activation response of the type II hexokinase gene to hypoxic conditions
AU - Mathupala, Saroj P.
AU - Rempel, Annette
AU - Pedersen, Peter L.
PY - 2001/11/16
Y1 - 2001/11/16
N2 - One of the most common signatures of highly malignant tumors is their capacity to metabolize more glucose to lactic acid than their tissues of origin. Hepatomas exhibiting this phenotype are dependent on the high expression of type II hexokinase, which supplies such tumors with abundant amounts of glucose 6-phosphate, a significant carbon and energy source especially under hypoxic conditions. Here we report that the distal region of the hepatoma type II hexokinase promoter displays consensus motifs for hypoxia-inducible factor (HIF-1) that overlap E-box sequences known to be related in other gene promoters to glucose response. Moreover, we show that subjecting transfected hepatoma cells to hypoxic conditions activates the type II hexokinase promoter almost 3-fold, a value that approaches 7-fold in the presence of glucose. Consistent with these findings is the induction under hypoxic conditions of the HIF-1 protein. Reporter gene analyses with a series of nested deletion mutants of the hepatoma type II hexokinase promoter show that a significant fraction of the total activation observed under hypoxic conditions localizes to the distal region where the overlapping HIF-1/E-box sequences are located. Finally, DNase I footprint analysis with a segment of the promoter containing these elements reveals the binding of several nuclear proteins. In summary, these novel studies identify and characterize a marked glucose-modulated activation response of the type II hexokinase gene to hypoxic conditions within highly glycolytic hepatoma cells, a property that may help assure that such cells exhibit a growth and survival advantage over their parental cells of origin.
AB - One of the most common signatures of highly malignant tumors is their capacity to metabolize more glucose to lactic acid than their tissues of origin. Hepatomas exhibiting this phenotype are dependent on the high expression of type II hexokinase, which supplies such tumors with abundant amounts of glucose 6-phosphate, a significant carbon and energy source especially under hypoxic conditions. Here we report that the distal region of the hepatoma type II hexokinase promoter displays consensus motifs for hypoxia-inducible factor (HIF-1) that overlap E-box sequences known to be related in other gene promoters to glucose response. Moreover, we show that subjecting transfected hepatoma cells to hypoxic conditions activates the type II hexokinase promoter almost 3-fold, a value that approaches 7-fold in the presence of glucose. Consistent with these findings is the induction under hypoxic conditions of the HIF-1 protein. Reporter gene analyses with a series of nested deletion mutants of the hepatoma type II hexokinase promoter show that a significant fraction of the total activation observed under hypoxic conditions localizes to the distal region where the overlapping HIF-1/E-box sequences are located. Finally, DNase I footprint analysis with a segment of the promoter containing these elements reveals the binding of several nuclear proteins. In summary, these novel studies identify and characterize a marked glucose-modulated activation response of the type II hexokinase gene to hypoxic conditions within highly glycolytic hepatoma cells, a property that may help assure that such cells exhibit a growth and survival advantage over their parental cells of origin.
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U2 - 10.1074/jbc.M108181200
DO - 10.1074/jbc.M108181200
M3 - Article
C2 - 11557773
AN - SCOPUS:0035900767
SN - 0021-9258
VL - 276
SP - 43407
EP - 43412
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 46
ER -