Background Numerous studies have shown that the intracellular redox potential of
ID: 274905 • Letter: B
Question
Background
Numerous studies have shown that the intracellular redox potential of the cell is important to cell growth. Cellular redox potential can be determined by the amounts of the reduced coenzyme NADPH, a principal product of the oxidative branch of the pentose phosphate pathway (PPP). The investigators in the study presented here sought to demonstrate links between the activity of the enzyme glucose-6-phosphate dehydrogenase (G6PD) activity, cellular NADPH concentrations, and rates of cell growth. Previous studies have shown that the glucose-6- phosphate dehydrogenase enzyme can be activated on the order of minutes or even seconds, possibly through the action of growth factors that release a bound, inactive G6PD to the cytosol, where, via a mechanism that might involve tyrosine phosphorylation of a membrane-bound receptor, the unbound G6PD translocates to the cytosol and becomes active.
QUESTION
In order to more conclusively show a link between G6PD and cell growth, the investigators transfected a cell line, COS-7, with the G6PD gene. The transfected COS-7 cells showed a 2- 3-fold increase in G6PD activity as compared to cells that hadn’t been transfected with the gene. The authors of the study then investigated the effect of the inhibitor DHEA on these transfected cells by measuring the amount of [3H]-thymidine incorporation into COS-7 and control cells. The results are shown in Figure 32.6. What is your interpretation of these results? Be quantitative. ?
200 control ? COS-7 cells 1 00 0 0.00 20.0 60.0 100. DHEA conc, -M Fiqure 32.6: The effect of DHEA, as measured by [3Hl-thymidine incorporation, was determined in COS-7 cels transfected with the G6PD gene, and compared to control cells (from Tian, et al. 1998).Explanation / Answer
From the figure above, we can see that with the increasing concentration of DHEA the proliferation rate of cells decrease as can be seen by decreasing incorporation of radiolabelled thymidine into DNA of the cells. Dehydroepiandrosterone, DHEA is regarded as a potent uncompetitive inhibitor of mammalian glucose-6-phosphate dehydrogenase (G6PDH), the rate-limiting enzyme in the pentose phosphate pathway. The consequence of this is low NADPH levels. NADPH which acts as a cofactor for NADPH oxidase plays an important role in cell proliferation. Thus lowering NADPH levels by treatment of cells with DHEA decreases the rate of cell proliferation.
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