New Role Found for Cancer Protein P53

ScienceDaily (Mar. 2, 2011) — The gene for the protein p53 is the most frequently mutated in human cancer. It encodes a tumor suppressor, and traditionally researchers have assumed that it acts primarily as a regulator of how genes are made into proteins. Now, researchers at the University of Pennsylvania School of Medicine show that the protein has at least one other biochemical activity: controlling the metabolism of the sugar glucose, one of body's main sources of fuel. These new insights on a well-studied protein may be used to develop new cancer therapies.

The tumor suppressor p53 inhibits glucose-6-phosphate dehydrogenase (G6PD) by catalytically converting the active dimer to an inactive monomer. Through the inhibition of G6PD, p53 suppresses glucose consumption and biosynthesis. However, tumor-associated p53 mutants lose this function, which contributes to the Warburg effect and enhanced biosynthesis in tumor cells. The background shows images of p53 and G6PD localization in the cell.

Intriguingly, Yang and his team estimate that the level of p53 is only about 3 percent that of G6PD. So in the cell, the p53/G6PD ratio is very low. But p53 has a dramatic effect on the overall activity of G6PD. This suggests that one p53 molecule can inactivate many G6PD molecules. This qualifies p53 as a catalyst. It appears to act almost as an enzyme to convert its much more abundant binding partner into an inactive form via transient rather than stable interactions.

Normally, when one protein binds to and inhibits another, that inhibition lasts only as long as the two proteins are bound together; dissolution of the complex almost invariably activates the released proteins. But in the case of p53 and G6PD, transient interaction with p53 is sufficient to convert G6PD into an inactive form -- a property that is most often associated with enzymes. Says Yang, this enables p53, which at most is present at 10 percent the abundance of G6PD, to regulate its binding partner.

"By converting G6PD from active to inactive form, p53 also has an enzymatic function," says Yang. That kind of mechanism, he says, is "totally new" for p53, and a new paradigm for signal transduction in general.

"This non-stoichiometric effect of p53 on G6PDH is intriguing as it proposes a catalytic role for p53, something that even in the p53 world, which is accustomed to occasional twists, is surprising," wrote Eyal Gottlieb of Cancer Research UK in an accompanying editorial.

Now, says Yang, the question is whether this new role for p53 can be exploited to yield novel anticancer therapies. "Previously," he says, "people were hesitant to target the inefficient pathway because they thought it was stimulatory. Our data suggests the pathway is a good target."

The research was supported by the China National Natural Science Foundation, the Chinese Ministry of Science and Technology, the Chinese Academy of Sciences, the US National Cancer Institute and the US Department of Defense. Peng Jiang, PhD, and Wenjing Du, PhD, postdoctoral fellows in the Yang lab, were co-first authors on the paper.