Your latest work involves tumor necrosis factor, or TNF. Tell us about that.

   Karin: One of the signals that activates the Jun kinase very strongly is TNF, and also interleukin one, IL-1. These are the major pro-inflammatory cytokines. What it means is that their expression is rapidly induced in response to infection or any kind of intrusion to a body, sometimes even in response to trauma. In return, they indirectly activate the transcription of a large number of other genes, which code for a large number of other immunoregulatory molecules—other cytokines, chemokines, adhesion molecules, and so on.

   That made me quite interested in TNF action, and it’s a topic that we’ve pursued on and off. We had an important paper back in 1991 showing TNF stimulates AP-1 activity and induces c-Jun expression. And then a new fellow joined the lab, Z.G. Liu, and he started looking at the mechanism by which TNF signals to the Jun kinases. He also looked at TNF-induced apoptosis. Basically he just outlined the three major signalling pathways activated in response to TNF. [See table, paper #4.] That was done in collaboration with Dave Goeddel's group at a company called Tularik.

   That work also put us in connection with another transcription factor that we worked on kind of on and off over years, NF-kB, which works together with AP-1 to coordinate among other things the response to inflammation.

   Some of those genes induced by TNF or IL-1 contain binding sites for either AP-1 or NF-k B and many contain binding sites to both of these transcriptions factors. We missed on the discovery of NF-kB. Most of the initial and seminal discoveries in the field were made by David Baltimore and his coworkers.

            What are the clinical implications of all these regulating molecules?

   Karin: There are actually major drug-discovery programs in quite a number of both big and small companies focusing on inhibitors for the Jun kinases, and now on inhibitors of NF-kB activation, which is mediated by the I-kB kinases. These important kinases were first discovered in our lab in 1996. At this point, the exact function of drugs that will inhibit the Jun kinases is uncertain. Everyone expects them to be anti-inflammatory because these protein kinases are involved in inflammation, but the inhibitors for the Jun kinases may also be neuro-protective. Another group has found that one of the Jun kinases is necessary for killing off neurons in response to trauma and excito-toxicity. And we have also shown that these kinases are activated in response to stroke, so one speculation is that such inhibitors may prevent cell death after stroke. So these protein kinases do a lot of things. Companies expect the inhibitors to work in one area or another, but the bottom line is we will never be sure until we have highly specific inhibitors and we can start testing them.

   As for NF-kB and the I-kB kinases, everyone expects their inhibitors to be anti-inflammatory, but back in ‘97 we also showed that NF-kB protects cells from apoptosis. So the possibility is that if you get too good of an inhibition of NF-kB you may start sensitizing cells to apoptosis. That could be a risk associated with the use of such inhibitors. On the other hand, it may provide an opportunity to sensitize cancer cells to chemotherapy and radiation therapy—certain leukemias and lymphomas, for example.

   This whole area—examining how cells protect themselves from various enviromental agents to either facilitate or protect from apoptosis—is very interesting for basic academic research and for important applications for human health. We are staying quite active in this area because, in theory, if you can block a pathway that is activated during the transformation process that protects a tumor cell from apoptosis, and that pathway is only activated in the tumor and not in normal cells, you might be able to turn on the apoptotic program only in the tumor. That should result in much "cleaner" and precise anticancer drugs.

            What would you like to accomplish in the next five years?

   Karin: We would like to identify signaling pathways that are activated during the transformation process to protect tumor cells from apoptosis. A lot of oncogenes not only stimulate cell proliferation but also activate the apoptotic program. In order to be good oncogenes they have to turn on something that will protect the cells from apoptosis. There may be some kind of Achilles’ heel for the transformation process, and if we find it we can turn back the activity of the oncogene against itself.

   The other thing is that over the past 15 years, from work done in our lab and others, we have learned a lot about how gene transcription is regulated in response to extra-cellular signals. But there is another level in which gene expression is regulated, and that's through regulation of mRNA turnover, and in comparison it’s pretty much a black box. We know very little about it. So we just started a project to look at how signaling pathways regulate mRNA stability.

            How would you describe your modus operandi over the years? What is it about your approach that sets you apart from your colleagues?

   Karin: First of all we try to stay one step ahead of the competition. I was once advised that it's a lot easier to be ahead of everyone; then you don't have to read a whole lot of literature. More seriously, it’s really just trying to understand the basic processes and how they're regulated, and using many different experimental approaches rather than a single approach. If it's something the lab has never done, we just learn how to do it.