Transcriptional control by NF-κB and DSIF and their modulation by drugs
NF-κB family of transcription factors plays key roles in immune and stress responses and its deregulation contributes to cancer and chroic inflammation. Therefore its modulation has become an important therapeutic target. By investigating NF-κB transcriptional activity we revealed novel connections between transcription initiation, elongation and mRNA processing. Specifically, NF-κB recruits the transcription elongation factor DSIF (Spt5/Spt4 complex) which is particularly important for a subset of NF-κB target genes. Furthermore, we found that in these genes DSIF performs a novel mode of coordination between initiation, elongation, mRNA splicing and export. Our studies uncovered previously unknown molecular features of DSIF and also defined it as an integral player in the negative feedback regulatory circuit of NF-κB.
Investigating NF-κB proteins at the biochemical level, we recently uncovered a novel allosteric mechanism of NF-κB dimerization and DNA binding.
Using high throughput drug screening, we identified several small moleculles that specifically interfere with NF-κB dimerization and with the allosteric domain. We have also identified drugs that specifically inhibit Spt5. These inhibitors are now being explored as potential anti-inflammatory and anti-neurodegenrative drugs.