Inflammation and Signal Transduction

The Section Research Programme

The research focus of the section is the Control of Programmed Cell Death by NF-κB/Rel Transcription Factors and its roles in Immunity, Inflammation and Cancer.

In addition to coordinating immune and inflammatory responses, NF-kB/Rel transcription factors control cell survival. Activation of NF-kB antagonizes apoptosis or programmed cell death (PCD) induced by TNFα. The anti-apoptotic activity of NF-kB is also crucial to oncogenesis and cancer chemo and radio-resistance, and serves a wide range of physiological processes, including B lymphopoiesis and B- and T-cell costimulation. This activity involves induction of protective genes; however, its bases remain poorly understood.

During the past few years, the group has focused on the identification and characterization of the anti-apoptotic genes that are controlled by NF-kB. This is of interest since, in addition to gaining insights into mechanisms of immune activation and oncogenesis, identification of these genes might provide new molecular targets for treatment of chronic inflammatory conditions and several malignancies such as Hodgkin’s lymphoma and multiple myeloma. Inhibitors of NF-B are routinely used to treat these diseases. However, these inhibitors (e.g. glucocorticoids and proteasome inhibitors) can only achieve partial inhibition of NF-kB and exhibit considerable side effects, including immunosuppressive effects, which limit their use in humans. Thus, a better therapeutic approach would be to block the critical anti-apoptotic targets of NF-kB, rather than NF-kB itself.

Genes that can block apoptosis and are controlled by NF-kB have been identified. These genes, however, do not appear to fully account for the anti-apoptotic activity of NF-kB. Previous screens aimed at identifying protective targets of NF-B have relied upon expression criteria, and this might explain why most genes isolated with these screens had already been known to have anti-apoptotic activity.

The group therefore devised a screening method that assayed for gene function, rather than gene expression. This method –known as the "death trap" – provides substantial advantages over other screens, also aimed at identifying these genes, as it ensures that isolated genes have anti-apoptotic functions. Foremost, it allows a functional assessment of candidate genes without any preconceived information about their sequences, and so represents an unbiased approach.