Journal News

JBC: How an interest in bipolar disorder drugs led to a better understanding of leukemia

Sasha Mushegian
April 01, 2018

A research project that began 20 years ago with an interest in how lithium treats mood disorders has yielded insights into the progression of blood cancers such as leukemia. The research, which centers on a protein called GSK-3, was published in the Journal of Biological Chemistry.

Lithium is considered a highly effective treatment for bipolar disorder and other mood disorders, but it still works in only a fraction of patients and has a number of side effects. Furthermore, its mechanism of action is poorly understood, hampering efforts to improve on it.

A new project reveals that the enzyme GSK-3, a target of the mood disorder drug lithium, has a role in controlling alternative splicing in cells. This observation may yield insights into leukemia. Courtesy of Mansi Shinde and Simone Sidoli

In 1996, Peter Klein of the University of Pennsylvania discovered that one of lithium’s biological activities was inhibiting GSK-3, an enzyme that modifies other proteins by attaching phosphate molecules, a process called phosphorylation. Lithium’s effect on GSK-3 affected the development of animal cells, but it is still unknown what connection, if any, this has to psychiatric disease.

Since then, Klein — now a professor of medicine at Penn — has been investigating many aspects of GSK-3 activity. “In this paper, we were trying to find out what proteins in the cell are affected by GSK-3 inhibition,” Klein said. “We compared cells with GSK-3 to cells completely lacking GSK-3 to ask how other proteins changed.”

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

The research team used mass spectrometry to compare phosphorylation of proteins from mouse embryonic stem cells with fully functioning GSK-3 to cells in which the gene encoding GSK-3 had been deleted. The resulting massive data set is called a phosphoproteome — a comprehensive catalog of proteins that are phosphorylated by GSK-3. Analyzing the data yielded some surprising findings.

Conventional wisdom had suggested that GSK-3 phosphorylates proteins that contain a specific amino acid sequence, but the new phosphoproteome showed that the majority of proteins whose phosphorylation depended on GSK-3 did not contain this sequence. Notably, the phosphorylated proteins included a group called splicing factors, which splice together different sections of messenger RNA, changing the proteins they encode. Absence of GSK-3 changed the splicing patterns of more than 200 messenger RNAs.

The finding that GSK-3 could affect RNA splicing pointed to an unexpected connection: leukemia. Several factors newly discovered to be phosphorylated by GSK-3 also are known to be mutated in acute myeloid leukemia, a condition in which aberrant splicing causes uncontrolled white blood cell proliferation. This observation could also explain why one of the side effects of taking lithium is increased white blood cell count.

“The effect on the splicing factors and other mutations associated with leukemia was completely surprising to me,” Klein said. The group now is pursuing investigations into how GSK-3 affects the growth of healthy and leukemic blood cells.

Shinde and Klein are not sure whether GSK-3’s effect on RNA splicing explains its role in mood disorders. The effect of GSK-3 on messenger RNA in neuronal cells, with or without lithium, would need to be examined to determine this. The study underlines how investigations into the basic biological function of a drug target can lead in unexpected directions. The GSK-3 phosphoproteome is “a really large data set,” Shinde said. “It’s a resource for the field.”

“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.”

Sasha Mushegian

Sasha Mushegian is a postdoctoral fellow at Georgetown University. Follow her on Twitter.

Join the ASBMB Today mailing list

Sign up to get updates on articles, interviews and events.

Latest in Science

Science highlights or most popular articles

Why you need more vitamin D in the winter
Wellness

Why you need more vitamin D
in the winter

January 26, 2020

With less exposure to sunlight in winter, adults should take in at least 600 international units per day of vitamin D from supplements or foods like oily fish, mushrooms and fortified dairy.

From the journals: MCP
Journal News

From the journals: MCP

January 25, 2020

Read about capturing a peptide link between migraines and opioid-induced sensitivity, profiling autologous body fluid exosomes and finding the RSK in melanoma protein interactions.

From the journals: JBC
Journal News

From the journals: JBC

January 24, 2020

Recent topics include misfolded tau proteins in Alzheimer’s disease, how enzymes trim peptides and how a parasite hijacks the immunity of its host.

Early immune response may improve cancer immunotherapies
Journal News

Early immune response may improve cancer immunotherapies

January 23, 2020

University of Illinois at Chicago researchers and colleagues report a new mechanism for detecting foreign material during early immune responses.

Do sperm offer the uterus a secret handshake?
Journal News

Do sperm offer the uterus
a secret handshake?

January 22, 2020

Why does it take 200 million sperm to fertilize a single egg? A female immune response is one reason. A molecular handshake may help sperm survive the bombardment.

A new hotspot for cyclooxygenase inhibition
Lipid News

A new hotspot
for cyclooxygenase inhibition

January 21, 2020

Drugs like aspirin dampen inflammation by inhibiting certain enzymes but can have nasty gastrointestinal side effects, so enzymologists are investigating the structure of the enzymes’ active sites in hopes of designing more selective inhibitors.