Blood Cell Maturation Depends on a Specific Ubiquitin Ligase

Cancer researchers have identified a protein that directs immature blood cells to either differentiate into mature red or white blood cells or to enter a pathway that leads to apoptosis.

Previous studies had shown that enzymes of the type known as Cul4A ubiquitin ligases regulated proliferation and differentiation in maturing blood cells. Embryos that lacked the gene for Cul4A died in utero from lack of blood cells.
In the current study, investigators at the Indiana University School of Medicine (Indianapolis, USA) examined the role of Cul4A in adult animals by genetically engineering a line of mice that could be induced to stop producing the enzyme by treatment with interferon.

Results published in the July 15, 2008, issue of the journal Blood revealed that Cul4A deficiency resulted in DNA damage and apoptosis of rapidly dividing cells. The genetically engineered mice died within 3 to 10 days after interferon induction with dramatic atrophy of the intestinal villi, bone marrow, and spleen, and with failure to produce mature blood cells. Bone marrow transplants into the modified mice failed to replace the missing blood cells, and the animals died 9 to 11 days after receiving the grafts.

"Our work is the first to show an effect in all blood cells and establishes that Cul4A is essential for the survival of blood cells and possibly other cells including cells of the intestine. It is still early in the scientific process but we know this protein is involved in many cellular pathways in the body. If we can learn about the pathway this protein takes, we may be able to develop targeted drug therapies that are better at attacking diseased blood cells and avoiding healthy ones,” explained senior author Dr. Kristin T. Chun, assistant professor of pediatrics, biochemistry, and molecular biology at the Indiana University School of Medicine.

"How cullin 4A regulates other proteins that control the fate of blood cells is important because when cullin 4A fails to regulate their degradation properly, blood cells die and this leads to bone marrow failure. There are many reasons why this is significant.” said Dr. Chun. "For example, when blood cells make wrong decisions the result can be a lack of a sufficient number of certain types of mature blood cells causing leukemia, anemia, or bone marrow failure.”

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Indiana University School of Medicine