A New Genetic Target for Preventing Tumor Growth

Peter Devreotes
Peter Devreotes
Scientists keep breaking down the steps of cancer, into smaller and smaller parts. For example, the process of making a tumor, and then having that tumor spread, or metastasize, involves chemical signals that go awry.

One very important signal that gets muddled is a lipid molecule called PIP3. Normally, two key enzymes keep this molecule on a pretty tight leash, and this control in turn, helps keep cell growth in balance. The two enzymes are P13K, and PTEN. "P13K is a ‘go' signal for cell growth and migration," like the accelerator on a car, explains Walsh Scholar Peter Devreotes, Ph.D., Professor and Director of the Department of Cell Biology, "while PTEN is the corresponding ‘stop' signal," or the brakes. Genes like PTEN, which normally keep cells in check, are called tumor suppressors.

Imagine trying to drive a car when
someone has tampered with the
brakes. That's what cell growth is
like in cancer — unchecked. But
what if we can fix the brakes?

"PTEN is one of the most frequently mutated tumor suppressors in prostate cancer," says Devreotes. When it is disrupted, the effect is like tampering with the brakes.

PIP3, the lipid molecule, lives on the cell's outer membrane. Although PTEN's job is to target this molecule, only a few PTEN molecules actually make contact with it at the surface of a cell. But scientists have figured out how to tweak PTEN through genetic engineering, and dramatically increase its ability to make contact with PIP3. This doctored version of PTEN is called PTENA4, and "it's proven to be much more effective than normal PTEN in providing a ‘stop' signal, by reducing the amount of the lipid PIP3," says Devreotes.

Devreotes and colleagues found that, in shape, PTEN contains a highly flexible tail, and guessed that PTEN could regulate itself by attaching, or binding, this tail to the rest of the protein. When the tail was bound, PTEN would be in a closed form; when it was released, PTEN would be in an open form. "The open form would bind more strongly to the membrane than the closed form," he says. "To test this hypothesis, we cut off the tail, and found that the binding of the body of PTEN to the membrane was indeed very strong, like that of PTENA4." Then the scientists found that the body and tail could bind tightly to each other.

This work suggests that controlling PTEN is critical in preventing tumor growth and formation. The next step is "to visualize the exact site where the body and tail regions of PTEN interact," Devreotes says. "By doing so, we hope this will allow us to target these regions, in order to open and activate PTEN, and allow for the possibility of restoring normal cell growth."

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