Stem-cell activators switch function, repress mature cells

December 16, 2009

In a developing animal, stem cells proliferate and differentiate to form the organs needed for life. 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 Ohio State University Comprehensive Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, shows for the first time that three proteins, called E2f1, E2f2 and E2f3, play a key role in the transition make to their final, differentiated, state.

These proteins help stimulate stem cells to grow and proliferate. But once stem cells begin to differentiate into their final cell type - a cell in the or in the lining of the , for example - the same three proteins switch function and stop them from dividing any more.

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 types of cancer, suggesting that these E2f proteins might offer a safe and novel therapeutic target in these tumors.

The findings are published in back-to-back papers in the Dec. 17 issue of the journal Nature.

"We show that these E2fs are gene activators in stem cells but then switch to gene repressors when stem cells begin differentiating," says Gustavo Leone, associate professor of , immunology and medical genetics at Ohio State's James Cancer Hospital and Solove Research Institute. Leone headed the first of the two Nature studies and is a co-author on the second.

"This is a very important step in the process of differentiation," Leone says. "As organs form during development, there comes a time when their growth must stop because an organ needs only a certain number of cells and no more. The switch by these proteins from activators to repressors is essential for that to happen.
"Before this, there was no suspicion that these regulatory proteins had any role in differentiated cells," says Leone. "It was thought they were important only in proliferating cells like stem cells. But that's not true."

Leone and his 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. "In this case, these proteins are acting abnormally relative to the surrounding tissue, so they might provide a safe therapeutic target," Leone explains. "If we can inactivate these E2fs in cancer cells, perhaps we can prevent further tumor growth without having a major affect on healthy cells."

Related Stories

Recommended for you

Natural compound reduces signs of aging in healthy mice

October 27, 2016

Much of human health hinges on how well the body manufactures and uses energy. For reasons that remain unclear, cells' ability to produce energy declines with age, prompting scientists to suspect that the steady loss of efficiency ...

A metabolic switch to turn off obesity

October 27, 2016

You've tried all the diets. No matter: you've still regained the weight you lost, even though you ate well and you exercised regularly! This may be due to a particular enzyme in the brain: the alpha/beta hydrolase domain-6 ...

Mitochondria control stem cell fate

October 27, 2016

What happens in intestinal epithelial cells during a chronic illness? Basic research conducted at the Chair of Nutrition and Immunology at the Technical University of Munich (TUM) addressed this question by generating a new ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.