A University of Minnesota-led research team has proposed a mechanism for the control of whether embryonic stem cells continue to proliferate and stay stem cells, or differentiate into adult cells like brain, liver, or skin.

The work has implications in two areas. In cancer treatment, it is desirable to inhibit cell proliferation. But to grow adult stem cells for transplantation to victims of injury or disease, it would be desirable to sustain proliferation until a sufficient number of cells have been produced to make a usable organ or tissue.

The study at the university’s Hormel Institute used mouse stem cells to give researchers a handle on how the two competing processes might be controlled.
The mechanism centers on a protein, Klf4, that is found in embryonic stem cells and whose activities include keeping those cells dividing and proliferating rather than differentiating. The researchers discovered that two enzymes, ERK1 and ERK2, inactivate Klf, allowing the cells to differentiate into adult cells.

The two enzymes are part of a “bucket brigade” of signals that starts when a chemical messenger arrives from outside the embryonic stem cells. Chemical messages are passed to inside the cells, resulting in the two enzymes swinging into action.

The researchers also discovered how the enzymes control Klf4. They attach a small molecule—phosphate, consisting of phosphorus and oxygen—to Klf4. The “tag” marks it for destruction by the cellular machinery that recycles proteins.

They found that suppressing the activity of the two enzymes allows the stem cells to maintain their self-renewal and resist differentiation. Taken together, the findings paint a picture of the ERK1 and ERK2 enzymes as major players in deciding the future of embryonic stem cells—and potentially cancer cells, whose rapid growth mirrors the behavior of the stem cells.

Klf4 is one of several factors used to reprogram certain adult skin cells to become a form of stem cells called iPS (induced pluripotent stem) cells, which behave similarly to embryonic stem cells. Many studies have shown that Klf4 can either activate or repress the functioning of genes and, in certain contexts, act as either an oncogene (that promotes cancer) or a tumor suppressor. Given these and the findings, the researchers suggest that the self-renewal program of cancer cells might resemble that of embryonic stem cells.

The research was published in Nature: Structure and Molecular Biology.

Release Date: Feb. 6, 2012
Source: University of Minnesota