Warburg effect

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this is a biochemical explanation for Warburg effect

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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.

Xiaolu Yang, PhD, associate professor of Cancer Biology at the Abramson Family

Cancer Research Institute, along with Mian Wu, PhD, at the University of Science

and Technology of China and Nanjing University, report in the current issue of

Nature Cell Biology that p53 controls a molecular crossroads in the cell's

glucose metabolic pathway.

They found that p53 physically binds to and inhibits an enzyme --

glucose-6-phosphate dehydrogenase (G6PD), which catalyzes the first step of the

pathway. If p53 can't do its intended job, cells grow out of control.

Blocking this pathway shunts glucose away from energy storage and towards making

genetic building blocks and lipids that contribute to cells' proliferation. p53

normally serves to dampen synthesis of molecules and cell reproduction by

forcing the cell to take up less glucose.

In tumors, more than half of which carry mutations in the p53 gene, this routing

function is abolished, enabling cells to build biomass and divide with abandon.

The findings provide a biochemical explanation for the Warburg effect, which

explains how cancer cells, regardless of type, seem inevitably to boost their

glucose consumption, but not in an energy efficient way.

" We found a connection between the most frequently mutated gene in cancer cells

and how that mutation contributes to tumor growth, " says Yang.

Making a Choice

When it takes up glucose, a cell has three choices: It can store the sugar, turn

it into energy, or use it to make nucleic acids and lipids. As Yang explains,

researchers have recognized for years that tumor cells consume glucose far

faster than non-cancerous cells, but also that they don't seem to use the most

energy efficient pathway to burn the fuel. What, then, were they doing with it?

Yang and his team found in both human colon cancer cells and fibroblast cells

from mouse embryos that loss of p53 leads to increased glucose consumption

though the energy inefficient pathway. This increase was associated with greater

lipid synthesis and increased activity of G6PD, the enzyme that p53 is supposed

to latch onto to shunt glucose into storage, not wild synthesis.

The team found that p53 binds directly to G6PD to inhibit its activity,

apparently by interfering with the ability of G6PD to form a molecular complex.

In contrast, p53 mutants lack this binding activity. In effect, demonstrating

the binding role of p53 is distinct from its function as a regulator of protein

transcription.

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.

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Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff)

from materials provided by University of Pennsylvania School of Medicine.

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Journal Reference:

Peng Jiang, Wenjing Du, Xingwu Wang, Mancuso, Xiang Gao, Mian Wu, Xiaolu

Yang. p53 regulates biosynthesis through direct inactivation of

glucose-6-phosphate dehydrogenase. Nature Cell Biology, 2011; DOI:

10.1038/ncb2172

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