Role Reversal

Stem cell activators switch function, repress mature cells

Gustavo LeoneIn a developing animal, stem cells proliferate and differentiate to form organs. A new study shows how a crucial step in this process happens and how a reversal of that step contributes to cancer.

The study, led by researchers at the OSUCCC – James, shows for the first time that three proteins – E2f1, E2f2 and E2f3 – play a key role in the transition that stem cells make to their final differentiated state.

These proteins stimulate stem cells to proliferate, but once the cells begin to differentiate into their final type, the proteins switch function and stop them from dividing.

The research also shows how these proteins can switch course yet again in cells that have mutations in the retinoblastoma (Rb) gene. Mutated Rb genes occur in many cancers, suggesting that E2f proteins might offer a safe therapeutic target in these tumors. “We show that these E2fs are gene activators in stem cells but then switch to gene repressors when stem cells begin differentiating,” says study leader Gustavo Leone, PhD. “This is a very important step in differentiation. As organs form, there comes a time when their growth must stop because an organ needs only a certain number of cells. The switch by these proteins from activators to repressors is essential.”

Before, no one suspected that these regulatory proteins had any role in differentiated cells, Leone says. “It was thought they were important only in proliferating cells like stem cells. But that’s not true.”

Leone and colleagues show the function of the proteins in differentiation in mouse embryos, retinas, lenses and intestines. They also show how the three proteins could revert back to gene activators in cancer cells and promote tumor growth in cancers with Rb mutations.

Published Dec. 17, 2009, in back-to-back papers in Nature.

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