I was a post-doctoral fellow in Michael Greenberg's lab and my main research interest was the molecular basis underlying neuroplasticity, particularly calcium- and neurotrophin-regulated gene expression in neurons. JNK had just been cloned in 1994 and Mike wanted to know if JNK plays a role in p75 NGF receptor signaling. After hearing Mike talking about JNK in the lab at least three times (three is the magic number), I decided to take it seriously and had a lunch conversation with various lab members including David Ginty. We decided that the project would not be too difficult and definitely worth a try. So I took this on as a "side project" to investigate a role for JNK in p75 NGF receptor signaling. I discovered that JNK and p38 are activated with NGF withdrawal in PC12 cells. Because NGF withdrawal induces apoptosis, these results led us to investigate the functional consequences of JNK/p38 activation in PC12 cell apoptosis.

Mike was the driving force who led me to start studying JNK. During the course of the study, we were fortunate to have Roger Davis as our collaborator and we had many discussions on the project. We knew that the field was very competitive and we had to work hard and fast. Roger was always there for discussion even when I called him late in the evenings and on weekends. From an intellectual standpoint, Daniel Storm also contributed greatly. It was during a discussion with Dan that I first came up with the idea that a balance between ERK1/2 and JNK/p38 is critical in NGF withdrawal-induced apoptosis in PC12 cells.

It was the first paper demonstrating a role for the stress-activated MAPKs-JNK and p38, in regulation of apoptosis. This was one of the first biological/physiological functions identified for these pathways. In addition, it was the first study to show that it is the balance between growth-factor-regulated survival pathways (ERK1/2 in this case) and stress-activated death signaling pathways (JNK and p38 in this case) that determines whether a cell shall live or die. In other words, cell survival and apoptosis are regulated by a balance between multiple signaling pathways. Since our initial report, these MAPKs (ERK1/2, JNK, and p38) have been implicated in cell survival/apoptosis regulation in a broad range of biological settings and cell types, including immune cells, cancer cells, and neurons.

There have been many subsequent studies to investigate the role of these MAPKs during development and for various diseases, including cancer, inflammation, and various forms of neurodegeneration, including stroke, Parkinson's disease, Alzheimer's disease, and seizure. We have also seen intense interest in elucidating the pathways leading to JNK/p38 activation and downstream events mediating the biological function of JNK and p38.

We hope these mechanistic studies will ultimately translate into strategies for treatment of specific diseases. Pharmacological inhibitors for the JNK/p38 pathways may be good candidates for the treatment of stroke, brain trauma, and Parkinson's disease. Interestingly, CEP1347, an inhibitor of the JNK pathway, is currently in clinical phase III trial for Parkinson's disease. Because there are multiple isoforms of JNK and p38, and these kinases play a critical role in many areas of normal physiology, inhibitors for pan-JNK or pan-p38 may cause serious side effects that compromise their use in chronic conditions. It will be important and useful to elucidate the role of different isoforms of the kinases in different disease models and make isoform specific inhibitors for disease treatment. For example, pharmacological inhibitors specific for JNK3, which is mostly expressed in brain, may be a better drug candidate than the pan-inhibitor CEP1347 in the treatment of chronic neurodegenerative diseases like Parkinson' disease.

Never ignore unexpected results; they often lead to the most important and novel discoveries. Sometimes a "side project" can become a main career line, and, above all, basic research can have a profound impact on human disease treatment.

Zhenghui Xia, Ph.D.
University of Washington
Seattle, Washington, USA