Understanding the structure of the FoxM1 protein and how it works could guide development of new cancer-fighting drugs

UCSC.edu | May 28, 2019 | Tim Stephens

Unregulated cell division is a hallmark of cancer, and one of the key proteins involved in controlling cell division is called FoxM1. Abnormal activation of FoxM1 is a common feature of cancer cells and is correlated with poor prognosis, metastasis, and resistance to chemotherapy.

Now researchers at UC Santa Cruz have determined the structure of this protein–a kind of “master switch” for cell division–in its inactive or “off” conformation. This new understanding of the structure of FoxM1 could ultimately be used to design new drugs that stabilize the protein in its inactive state and thereby stop the uncontrolled proliferation of cancer cells.

Seth Rubin, professor of chemistry and biochemistry at UC Santa Cruz, explained that FoxM1 is a “transcription factor,” a protein that controls the activity of specific genes.

“When a cell is going to divide, there are a bunch of proteins that need to be made, and FoxM1 controls all the genes for those proteins,” Rubin said. “Because cancer cells are proliferating and dividing all the time, they need to activate FoxM1, so it has long been a target for drug development.”

The new study involved a close collaboration between Rubin’s lab and that of Nikolaos Sgourakis, assistant professor of chemistry and biochemistry. After determining the structure of the protein in the “off” state, the team then figured out how it switches from the inhibited conformation to the activated or “on” state. The researchers published their findings May 28 in the journal eLife.

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