Cellular transformation is associated with an increase in GLUT1 gene expression: Role of posttranscriptional regulation

Elevation of glucose transport is among the most characteristic biochemical markers of cellular transformation. The molecular mechanisms responsible for this alteration are unclear but accumulating evidence suggests that the accelerated rate of glucose transport in transformed cells is associated with increased expression of GLUT1 glucose transporter.;The studies described in this thesis examine a putative molecular mechanism underlying an increase in glucose transport capacity in mouse fibroblasts transformed by simian virus 40 large T-antigen (Tag) or Ha-ras oncogenes, as well as in cells progressively transformed by the expression of increasing levels of Tag. These investigations demonstrate that increase in the glucose transport capacity in transformed cells is associated with a concomitant significant increase in the abundance of GLUT1 transporter protein, associated with a significant increase in the steady-state levels of GLUT1 messenger RNA and increased GLUT1 mRNA stability. The results further indicate that the increase in GLUT1 mRNA stability is associated with a concomitant increase in the sequence specific complex formation between a cytoplasmic ribonuclear binding protein (RBP) and the AU-rich regulatory element within the GLUT1 mRNA 3' -UTR. Collectively, the data suggest that the transformation-induced increase in GLUT1 gene expression is due to an alteration in post-transcriptional regulation, such that the stability and levels of GLUT1 mRNA and, consequently, levels of GLUT1 protein are elevated via a pronounced increase in RBP/GLUT1 3'-UTR complex formation. Data suggest that this process is common to cells transformed by different classes of oncogenes and is progressively altered in transformed cells with progressive degrees of transformation. It is therefore proposed that post-transcriptional stabilization of GLUT1 mRNA via an increase in RBP/GLUT1 3'-UTR complex formation, leading to increase in GLUT1 gene expression, represents a mechanism responsible for activation of the glucose transport system in transformed cells. This study contributes to our knowledge of a possible molecular mechanism underlying the altered glucose transport in transformed cells and presents a possible target for therapeutic intervention.