Interaction Between BCL6 and Cytokine Signaling

Rothman, Paul

Abstract

The BCL-6 gene is the locus where breakpoints involving chromosomal translocations in 30-40 percent of diffuse large cell lymphoma and 6-11 percent of follicular lymphoma are found. These translocations lead to dysregulated expression of BCL-6 by juxtaposing heterologous promoters upstream of BCL-6 coding sequences. The product of the BCL-6 gene is a POZ/Zinc-finger protein that is expressed in germinal center B cells. Recent evidence suggests that BCL-6 can act as a sequence-specific repressor of transcription. However, the target genes for this activity have not yet been identified. Interestingly, the optimal binding site for BCL-6 defined in vitro shares striking homology to the GAS sites that are the target sequences for the cytokine-induced STAT (Signal Transducers and Activators of Transcription) signaling molecules. EMSA reveal that BCL-6 can bind to the binding site of the IL-4 activated protein, Stat6. Using reporter constructs with Stat6 binding sites we find that BCL-6 can repress IL-4 induced transcription. In addition, this repression is dependent on the POZ/repressor domain located at the amino terminus of BCL-6. Therefore, genes regulated by STAT binding sites may be one class of targets for BCL-6 mediated transcriptional repression. Germinal center B cells are exposed to an array of cytokines during an immune response. The repressor activity of BCL-6 may perform an important role in regulating the responsiveness of these B cells to cytokines and thereby act to modulate B cell differentiation. To determine the importance of BCL-6/STAT interactions we propose to: 1) Determine if BCL-6 represses the ability of different STAT molecules to activate transcription; (2) Explore the mechanism by which BCL-6 represses STAT function; 3) Determine if mice lacking BCL-6 have altered responses to cytokines; 4) Determine if BCL-6 transgenic mice have altered responses to cytokines.