In the early 1990s, Roger Davis had been studying cellular responses to hormones but decided to look at a bigger picture: cellular responses to stress. “We wanted to know if there is something fundamental that the body does in response to stresses of different kinds,” he says.
Davis and colleagues discovered a set of proteins that orchestrate a cell’s reaction to a range of stresses, including UV light, cancer, overactive immune systems, and even poor diet. Davis originally dubbed the proteins stress-activated protein kinases. They’re now called JNKs (c-Jun N-terminal kinases). These proteins are part of a larger group called MAP (mitogen-activated protein) kinases. The first MAPs discovered were found to trigger cell division. Davis found that JNKs, however, do something very different.
“Not much was known about MAP kinases when I started,” says Davis. “Then, everyone worked on the same few MAP kinases. We extended the work to find new ones. Initially, we called them stress-activated MAP kinases. But we found that instead of making cells grow, these proteins make cells stop growing, and even kill cells.”
It’s now known that there are 3 JNK genes in humans and at least 10 JNK proteins. Many stressful events activate JNKs. Eating a cheeseburger might do it. Taking a drug almost definitely does it. High blood pressure, cancer, inflammation, and bacterial infections all activate JNKs.
Davis and others then searched for JNK-activated pathways in cells to see what the JNK proteins were doing. They found that these proteins had their fingerprints all over a myriad of diseases and conditions.
In situations where cells are deprived of oxygen—such as a stroke, organ transplant, or heart attack—a JNK-activated pathway eventually leads to the death of the affected cells. In type 2 diabetes, a JNK-activated pathway changes the way the body responds to insulin.
Davis also has published work advancing the understanding of how JNK genes are involved in tumor formation. Mice lacking JNK genes were more likely to have tumors. Davis discovered that the JNK proteins helped tumor cells to die; without them, tumors grew.
In 2000, Davis and colleagues found that mice lacking two JNK genes could survive otherwise lethal doses of UV radiation.
Now, Davis and others are looking for drugs that can turn off JNK genes. This would shut down several destructive pathways that lead to damage and disease.
Davis hopes that such drugs are successful in clinical testing. But his more basic research has hardly reached a standstill. “I want to know the precise chain of molecular events” that leads to cell death. “If we can understand the molecular details, we could design better drugs that have specific effects—without side effects,” he says.
His research has led to better tools and techniques, so that now Davis and colleagues can manipulate the JNK pathway in one tissue type at a time in a single mouse. This helps them discover which cells ultimately control the stress response.
“In many diseases, such as type 2 diabetes, different tissues communicate. Fat communicates with liver and muscle. The brain communicates with liver, muscle, and fat,” he says. “[JNK] genes work in the tissues to mediate that,” Davis says. “The trick is to find out what’s driving the communication.”
JNK genes don’t work alone. Davis has found that scaffolding proteins called JIPs (JNK-interacting proteins) assemble JNK proteins and other proteins into molecular machines, which then travel around a cell.
He’s found that in neurons, these JIP complexes may communicate between synapses and the cell body to regulate gene expression. They also may be intimately involved in another hot-topic area of medicine: learning and memory.
“Mice that don’t have JIPs also don’t remember things,” says Davis. “We find that a very interesting aspect of our research.”