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Dietary glucose affects the levels of a powerful oncogene in mice
Date:11/14/2012

>In the study, the researchers sought to understand how to reduce the levels of proteins generated by mutations of the p53 gene in tumors. The issue is important, Avantaggiati says, not only because the majority of human tumors contains too much mutant p53 protein, but also because researchers now believe that current chemotherapy drugs actually increase the amount of mutant p53 in cancer, leading to possible resistance to these drugs.

In the five-year study, conducted in collaboration with her GUMC colleagues and co-authors Chris Albanese, Ph.D., and Olga Rodriguez, M.D., Ph.D., the researchers studied the link between glucose restriction and autophagy in cultured cells. Autophagy is a process that clears a cell of damaged organelles and misfolded proteins proteins viewed to be dysfunctional.

"Mutant p53 proteins are misfolded, but they are usually not efficiently degraded. However, when autophagy is induced by glucose restriction, this process eliminates them, and this is what we were hoping to see," Avantaggiati says. But the process offers an additional bonus. Autophagy is usually turned-off by mutant p53, but because these cancer cells now contain very little p53 protein, autophagy marches on, chewing up proteins, pushing the cancer cell to die.

The researchers then conducted a series of studies to see if this link could be established in animal models. In a transgenic mouse model with mutant p53, they showed that in mice fed a low carbohydrate (low glucose) diet but one with a normal calorie load there was a significant decrease in the amount of mutant p53 protein in their tissues, compared to mice fed with a high carbohydrate diet.

This suggested that mutant p53 levels are sensitive to glucose restriction, but additional research was needed to determine whether this phenomenon had an impact upon tumor growth.

To help answer that question, other experiments were conducted to test the ability of human lung ca
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Contact: Karen Mallet
km463@georgetown.edu
Georgetown University Medical Center
Source:Eurekalert

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