Scientists identify gene that causes good protein to turn bad

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There exists a protein that, most of the time, helps keep the growth of cancer cells in check. But every so often it does the opposite—with potentially deadly consequences.

But now, researchers have discovered precisely why this protein, known as TGF-beta, can perform such an abrupt about-face. The results, published today in the journal Science Signaling, shed light on potential therapies that can succeed where others have failed—and attack the most aggressive forms of cancer.

TGF-beta is a type of tumor suppressor, a protein that normally keeps cells from growing, dividing and multiplying too quickly, which is how most tumors originate. But scientists have long observed that in many forms of cancer, TGF-beta has switched sides: it becomes a tumor promoter fostering the out-of-control growth of cells.

In this study, scientists at the University of Michigan Comprehensive Cancer Center have figured out that a gene called Bub1 seems to be pulling the strings—essentially flipping the switch on TGF-beta. The finding that Bub1 played such an important role in regulating TGF-beta caught the team completely off guard. According to the paper’s senior author Alnawaz Rehemtulla:

“Bub1 is well-known for its role in cell division. But this is the first study that links it to TGF-beta. We think this may explain the paradox of TGF-beta as a tumor promoter and a tumor suppressor.”

The team reached this conclusion by screening gene candidates against lung cancer and breast cancer cells. After screening over 700 genes, they narrowed down the potential gene to Bub1.

Further experiments revealed that Bub1 physically binds to TGF-beta, turning it to a tumor promoter in the process. And when the team prevented Bub1 from binding to TFG-beta, essentially blocking it, TGF-beta never turned sides.

These initial results have left the research team optimistic, in large part because Bub1 is known to be active, or ‘expressed,’ in so many forms of cancer. So, if they can find a way to block Bub1 in one type of cancer, they may be able to do so with other types.

Even at this early stage, the team has developed a compound that could block Bub1. Initial lab tests show that this so-called Bub1 ‘inhibitor’ could shut off the gene without affecting surrounding regions. Said Rehemtulla:

“When you look at gene expression in cancer, Bub1 is in the top five…. But we never knew why. Now that we have that link, we’re a step closer to shutting down this cycle.”

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