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Monday, March 14, 2011

New role for p53

The p53 gene, named for the size of its protein (53 kilodaltons), is the most frequently mutated gene in human cancers. Normally, p53 functions as a ‘tumor suppressor’ regulating other genes involved in growth. Researchers from the University of Pennsylvania and the University of Science and Technology of China have discovered that p53 also plays an important role in glucose metabolism.

Glucose can be stored as a sugar, turned into energy, or used in the production of nucleic acids and lipids. The first enzyme in the glucose metabolism pathway is called glucose-6-phosphate dehydrogenase (G6PD). G6PD is also the rate-limiting step of the entire pathway, meaning that the speed of glucose turnover depends largely on the amount of available G6PD.

The researchers found that wild-type (normal) p53 proteins bind to and inactivate G6PD. This in turn limits the amount of glucose that the cell can take up. Mutant p53 does not bind to G6PD. This goes a long way to explaining why tumor cells, which are very often p53 mutants, tend to take up glucose so much more quickly than healthy cells, something that has long puzzled oncologists.

Even more intriguing, p53 appears to function as an enzyme itself. After binding to p53, G6PD is converted to an inactive form and remains in that form even after p53 releases it. In other words, p53 has catalyzed a change in G6PD. You only need 3% as much p53 as G6PD in a cell to dampen the glucose metabolism pathway, but without functional p53, the cells can process glucose with abandon.