Study Identifies Protein That Regulates Cell Differentiation

Illinois researchers have identified a protein that shuts down expression of hundreds of genes associated with differentiation, keeping pluripotent cells in a stem cell-like state.

Embryonic stem cells and other pluripotent cells divide rapidly and have the capacity to become nearly any cell type in the body. The mechanism by which such cells stop dividing and differentiate into their final cell type is not well understood but is highly relevant to understanding normal development and may be useful in cancer research.

A study led by University of Illinois Urbana-Champaign cell and developmental biology professor and department head Supriya Prasanth has found that, when the protein BEND3 is downregulated, cells adopt a final form and function—and, once they differentiate, they usually stop actively proliferating.

“In most cancers, cells are going through this rampant proliferation because cell-cycle regulators are not functioning properly,” Prasanth said. “The prognosis of how cancer cells will respond to treatment often relates to its status of differentiation. The more differentiated a tumor is, the better the prognosis.”

Stem cells also have the capacity to repopulate a cancer tumor after it has shrunk during treatment, Prasanth adds. Finding a molecular switch that will shift cancer cells away from proliferation and toward differentiation could aid in cancer treatment.

Prasanth’s earlier work identified BEND3 as a potentially important player in cell differentiation. Her team found that when BEND3 bound to strategic locales along the chromosome, it reduced or blocked the expression of dozens of genes. When BEND3 was removed, gene expression rebounded.

In the recent work, published in Proceedings of the National Academy of Sciences, Prasanth and her colleagues found that many of the genes repressed by BEND3 promote cell differentiation. “The binding of BEND3 to these genes blocks their expression, preventing the cells from entering a differentiated state,” she said. “And the moment you remove that control, the cells are now moving toward the differentiation pathway.”

BEND3 is not the only regulator of the cell-differentiation pathway; it binds to and interacts with many other molecular regulators of this process. But its presence or absence appears critical to determining a cell’s fate, making it an attractive target for potential medical interventions when the process goes awry.

In an accompanying paper published in the journal Genes and Development, the Prasanth lab and collaborators at the Memorial Sloan Kettering Cancer Center provided structural insights into BEND3-mediated gene regulation.