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Research suggests molecular 'switch' may play role in tumor suppression
Date:1/13/2013

llular distribution, this work will spur further research into unanticipated roles for this important molecule in healthy and diseased cells."

In endocytosis, trimeric clathrin molecules bind together to form molecular packages that allow other substances to enter cells. Several years ago, researchers in Japan published evidence that clathrin can also serve as an activator of the protein p53, a known tumor suppressor.

For the activation to take place, clathrin and p53 must both be present in the cell's nucleus. The catch is that clathrin molecules cannot penetrate the nucleus in their usual, three-legged form. To enter, the three-legged clathrin molecule must be altered or "de-trimerized."

Using X-ray crystallography, Ybe and his team discovered a "topology switch" in the clathrin molecule. They showed they could break the switch by mutating one key amino acid that is part of the switch. The result: Clathrin was "detrimerized"; three-legged molecules were broken into one-legged ones.

Experimenting with both cancer and non-cancer cells, the researchers found the three-legged clathrin only in the cytoplasm of the cells, not the nucleus. But with the "switch" broken, clathrin formed monomers and was also present in the nucleus, where it could potentially activate tumor suppression.

Ybe said the results point to the need for additional research to better understand the structure and function of clathrin and the role it plays in cellular processes, including those involved in cancer. With the clathrin "switch" identified, researchers can attempt to better understand how it can be activated, with the goal of developing new therapies for suppressing the growth of tumors. Ybe has a patent pending on the idea to use the mutated form of clathrin to stimulate the natural anti-cancer activities of human cells.

The finding developed from Ybe's research on the role of clathrin in Huntington's disease, a genetic disorder that c
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Contact: Steve Hinnefeld
slhinnef@iu.edu
812-856-3488
Indiana University
Source:Eurekalert

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