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Chemists unlock secret to activating tumor suppressor gene

University of Illinois at Chicago

Researchers have discovered the way to activate a key anti-cancer signal that goes AWOL in several gynecologic and brain cancers.

Since the late 1990s, researchers have known that a gene called PTEN (short for phosphatase and tensin homolog on chromosome 10) encodes a signaling protein that suppresses tumor growth. What wasn't known, however, was what mechanism activated PTEN. The answer was found by a group of researchers led by University of Illinois at Chicago chemistry professor Wonhwa Cho. They report their findings in the June 9 online edition of the Proceedings of the National Academy of Sciences.

"The role of PTEN is to counterbalance the action of an enzyme that induces cell growth," said Cho. "Over-activation of the enzyme can lead to cancer. So if you lose a PTEN gene and its cellular activity, the cell goes out of control. It's like a car with an accelerator but without the brakes."

It was generally thought that PTEN was activated by binding to other proteins, giving it a signal to interact with the cell membrane. But Cho said that's not the case.

Cho's group found that PTEN itself can be activated by phosphorylation, or the chemical addition of a phosphate tag.

"We found that the phosphorylation of certain sites of the PTEN protein worked as a switch to completely change its electrostatic property," said Cho. "It switched from being neutral to positively charged, then recognized the opposite charge on the membrane to bind there." Once the bind took hold, the cancer suppression action went to work.

Cho's laboratory used a biophysical technique called surface plasmon resonance analysis and cellular microscopic analysis of green fluorescence protein-labeled PTEN to unlock the secret of its activation. The UIC chemist believes the mechanism described for PTEN is a relatively common way to regulate membrane binding and activation of many cellular proteins involved in cell signaling and membrane trafficking.

Loss of PTEN regulation has been linked to various cancers, including the malignant and usually deadly brain cancer glioblastoma, and to endometrial carcinoma, or cancer of the uterine lining. It has also been linked to a cancer-prone condition called Cowden disease.

With this newly reported knowledge about the inner workings of PTEN, Cho hopes a way will be found to treat patients with damaged or mutated PTEN genes.

Loss of PTEN action causes the cancer, Cho explained. To treat this condition, one must add the PTEN gene to the cell which lacks it, but the resulting PTEN protein must be in its active form, he said.

"We discovered what activates the protein and can actually provide activated PTEN. We also discovered how PTEN rapidly degrades in a cell and can control the degradation. This may lead to a very effective therapy."


Other investigators on the study include Sudipto Das, a Ph.D. student in chemistry at UIC, and Jack Dixon, a professor formerly at the University of Michigan and now at the University of California, San Diego. Dixon has done extensive research on PTEN.

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