Stem-Cell Activators Switch Function, Repress Mature Cells

One of the mysteries of stem cell biology is how these cells can on the one hand make copies of themselves (called self-renewal), and depending on the needs of the body, become different cells, a process called differentiation. It is known that the process of differentiation is dependent on various chemical signals. For example, if one climbs on a mountain, the lack of oxygen stimulates cells within the kidney to make the hormone erythropoietin which increases the number of bone marrow stem cells that differentiate into red blood cells. While some of the signaling proteins are known, the effector proteins inside the stem cell that dictate its activity are still not very well understood.

In two recent back-to-back publications in the Dec 17 issue of Nature, some progress was reported in the understanding of stem-cell growth and differentiation. It was demonstrated that there exist three critical proteins which first stimulate stem cells to proliferate. Then, as the cells differentiate into their final cell type, these proteins switch function and arrest the cells from dividing any more. Because of their central role, the proteins could offer a safe and novel therapeutic target in many cancers. The proteins that arrest the multiplication of the cell may be considered as "tumor suppressor" proteins.

The published study, which was led by researchers at the Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, demonstrated that three proteins, called E2f1, E2f2 and E2f3, play a fundamental role in the differentiation steps that stem cells undergo as they lose their self-renewal activity. One of the interesting findings of the studies was the importance of the Rb tumor suppressor protein in blocking self-renewal of stem cells that are differentiating.

"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 molecular virology, 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."

Another interesting finding was that the E2f1, E2f2 and E2f3 proteins, while being inhibited in differentiated cells, can actually be re-activated in the presence of mutated tumor suppressor genes and lead to unrestricted cell growth. This provides another method of generating cancer cells in vitro for testing.

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