Research in the Jan. 26, 2007 issue of Cell describes a new cellular inhibitor of NFkB that provides a molecular link between development, inflammation, and possibly, cancer.

NFkB - which is not a single protein but rather a family of DNA binding proteins — is "probably the strongest transcriptional activator in mammalian cells," senior author Alexander Hoffmann told BioWorld Today.

When it is active, that is. Because it is such a strong activator, NFkBs binding to DNA is tightly regulated. That regulation falls to another protein family, the inhibitory IkB's. The IkB's are something like the administratium of the cell; "In resting cells, IkB and NFkB form a complex, and that complex sits around and doesn't do anything," Hoffmann explained.

However, in both development and inflammation, cellular signals can degrade IkB's, and when they do, NFkB springs into action, binding to regulatory gene sequences and initiating the transcription.

Hoffmann, assistant professor of biochemistry at the University of California, San Diego, and his colleagues at UCSD, the Salk Institute for Biological Studies, and the La Jolla Institute for Allergy and Immunology, all in La Jolla, Calif., had developed a mathematical modeling system that could describe and predict the different interactions between NFkB and IkB proteins, and were using it to study the developmental part of NFkB's work.

During development, NFkB signaling is necessary to stimulate the formation of lymph nodes and other organs, and "the organs that are required for adaptive immune defenses require some level of inflammation" even in adulthood, Hoffmann said. In a drastic case of 'use it or lose it,' adult mice that have their developmental NFkB signaling disrupted end up losing their lymph nodes.

Hoffmann and his team found that though developmental signals did indeed induce NFkB activation, they did so without apparent degradation of any of the three known IkB's. A mix of cell culture and mathematical modeling experiments revealed a fourth member of the IkB family, p100, that is degraded in response to developmental-type NFkB activating signals.

However, p100 also plays a role in the inflammatory pathway. When the scientists stimulated cells with the inflammatory signaling molecule tumor necrosis factor, or TNF, either in their modeling or in cell culture, this treatment shifted the balance of NFkB inhibition towards p100. These effects long outlasted any effects that TNF had on the inflammatory NFkB pathway, making it, the researchers write, "not only... an example of signaling crosstalk but also of cellular memory."

Besides providing a molecular mechanism for NFkB's developmental effects, the link between the developmental and inflammatory NFkB pathways also suggests a new way of targeting cancer, though Hoffmann cautioned that this is "a hypothesis that remains to be tested."

Nevertheless, many cancer cells have elevated NFkB activity, which makes them less likely to undergo apoptosis and hence, resistant to chemotherapy.

Hoffmann's mathematical model predicted that p100 would be highly expressed in cancer cells, which should in turn provide inhibition of NFkB, nudging cells towards apoptosis. But, he said, that doesn't happen.

His conclusion is that "cancer cells must be receiving some developmental signal that is degrading [p100]."

Targeting such a developmental signal, once it has been confirmed experimentally and identified, might be a comparatively easy way to shut down NFkB signals for two reasons. For one thing, developmental signals tend to be extracellular, making them easier to target from a drug delivery standpoint. For another, the developmental NFkB signaling is comparatively dispensable, at least for the duration of a cancer therapy run: "shutting down developmental signals is not as deleterious as shutting down innate immunity for a few weeks, which is what people are trying to do now."

Hoffmann also noted that for drug discovery researchers, the utility of his paper may not lie just in the results, but also in the approach of using mathematical modeling integrated with biochemical experiments: "Virtual reality is very powerful in testing drugs," Hoffmann said. Reconstructions of regulatory networks can help understand the ways that regulatory proteins, and the drugs developed against them, can reverberate through cellular networks.

However, while mathematicians tend to appreciate the power of modeling, many biochemists tend to not make full use of the technique themselves. Hoffmann hopes that his example shows that the two approaches can be integrated: "We're biochemists, and in our group, experiments and simulations are done side by side."