MOLECULAR MECHANISMS FOR REGULATION OF MAMMALIAN GLUCOSE TRANSPORTER EXPRESSION AND ITS FUNCTION

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Glucose uptake in mammalian cells is mediated by an integral membrane protein called as a glucose transporter which is an N-linked glycoprotein with molecular mass of about 50 kDa.We have previously demonstrated that glucose uptake in mammalian cells is regulated by growth factors-dependent expression of a brain-type glucose transporter GLUT1 as well as its glycosylation change which modulates affinity to D-glucose.In the present research we have studied changes in GLUT1 expression in human tumor cells using human cell hybrids which have provied an evidence that the tumorigenicity of a cervical carcinoma HeLa is under the control of a putative tumor suppressor in chromosome 11, and found a tumor-associated glycosylation change in GLUT1.An non-tumorigenic HeLa x fibroblast cell hybrid expressed the 50-55 kDa GLUT1, whereas in a tumorigenic segregant, GLUT1 glycosylation was altered and its molecular mass was about 70 kDa.Further studies on the oligosaccharides revealed that this glycosylation change in GLUT1 was mainly due to the increase in N-acetyl-lactosamine repeats in the oligosaccharides.In accordance with altered glycosylation, affinity for 2-deoxyglucose in the tumorigenic hybrid cells increased 2-fold, but there was little change in the Vmax.These results suggest that there may be a functional role for the modulation of GLUT glycosylation in the tumorigenic behavior of human tumor cells.Subsequent studies on these human cell hybrids indicated that expression of another integral membrane protein caveolin, which is a major component of a caveolae structure in the plasma membrane, decreased in a tumorigenic hybrid cells.Further studies on the role of this caveolin expression in tumorigenicity and tumor suppressor function of HeLa cells are carried out.