Study Investigates the Effects of GSK-3 Inhibition to Improve Understanding of Leukemia

In previous research, Peter Klein, MD, from the University of Pennsylvania, had found that one of lithium’s biological activities was inhibiting GSK-3. Klein recently investigated what proteins in the cell are affected by GSK-3 inhibition by comparing cells with GSK-3 to those lacking GSK-3, and the findings have implications for understanding leukemia.

The study, published in the Journal of Biological Chemistry, used mass spectrometry to compare phosphorylation of proteins from mouse embryonic stem cells with functioning GSK-3 to cells where the gene encoding GSK-3 had been deleted. From this, the researchers analyzed the phosphoproteome dataset, a catalog of proteins that are phosphorylated by GSK-3.

“Mood disorders are so multifaceted in terms of the pathways and pathologies involved; it's really difficult to pin down a specific pathway,” stated Mansi Shinde, PhD, a former graduate student in Klein’s research group who led the new study. “We said: Let's look at what GSK-3 does, and that would maybe lead us toward what lithium does.”

The analysis revealed that the majority of proteins whose phosphorylation depended on GSK-3 did not contain the specific amino acid sequence that GSK-3 phosphorylate proteins typically contain. The phosphorylated proteins had a group of splicing factors, which spice different sections of messenger RNA and change the proteins that they encode, according to the study.

The finding that GSK-3 could affect RNA splicing revealed a connection to leukemia, as many factors discovered to be phosphorylated by GSK are also mutated in acute myeloid leukemia. The researchers inferred that this could explain why increased white blood cell count is a side effect of taking lithium.

“The relevance to leukemia could be direct and something worthy of immediate study,” Klein said. “The role in psychiatric disorders is a major interest of the work, but the impact would be down the road, not immediate.”

The researchers are now looking to investigate how GSK-3 affects the growth of healthy and leukemic blood cells. Therefore, the effect of GSK-3 on messenger RNA in neuronal cells, with or without lithium needs to be examined.