Columbia University Health Sciences

Division of Pulmonary, Allergy & Critical Care

Divisional Research Activities

The Laboratory of Dr. Paul Rothman

The work in our group centers on several projects directed at understanding the role cytokines and cytokine signaling plays in both normal lymphocyte development and leukemic transformation. One project involves the study of the molecule mechanisms that control immunoglobulin heavy chain class switch recombination. Our experiments have found that different cytokines activate transcriptional activity of a specific heavy chain loci prior to recombination to those regions and we have proposed a model by which this transcription may target specific regions for recombination. Our present approach to address this model is to use homologous recombination to mutate the murine immunoglobulin heavy chain locus in B cells lines and in embryonic stem cells in order to generate genetically engineered (transgenic) mice that can be used to assess the role of different DNA elements in the switching process.

Another major project in the lab is trying to understand the role cytokine responsiveness plays in the development of T cell responses. We have shown that the ß component of the IFN-gamma cell surface receptor is regulated during the differentiation of naive THp helper CD4+ T cells into TH1 (IFN-gamma producing) cells. We believe that the regulation of this receptor component may be essential for the development of TH1 cells. We are pursuing this model using transgenic techniques to manipulate the levels of this receptor during T cell development.

A third major group in the lab is trying to understand the mechnisms underlying the ability of the v-abl oncogene to transform pre-B cells. We have found that pre-B cells that are transformed by the Abelson Murine Leukemia Virus have activation of the IL-4 and IL-7 signaling pathways in the absence of these cytokines. We are extending this work to understand in more detail how this kinase is activating these pathways.

The fourth major project in the lab centers on trying to understand how cytokines signal cells to activate transcription. Many of the effects of cytokines are mediated by their ability to regulate the transcription of target genes. We have centered our studies on IL-4. We have performed structure/function analysis of both the IL-4 receptor and the IL-4 inducible factor, Stat6. In the future, we will continue to identify new proteins involved in IL-4 signaling and define the mechanisms by which activation of these factor leads to the biologic activity of IL-4.

Finally, we have begun studying how the BCL-6 oncoprotein regulates cytokine signal transduction. The product of the BCL-6 gene is a POZ/Zinc-finger protein that is expressed in germinal center B cells. Although recent evidence suggests that BCL-6 can act as a sequence-specific repressor of transcription, the target genes for this activity have not yet been identified. In collaboration with Ricardo Dalla Favera at Columbia, we have shown that the optimal binding site for BCL-6 shares striking homology to the binding sites of the cytokine-induced STAT signaling molecules. BCL-6 can repress Stat6 activation of reporter constructs and the IL-4 induction of gene transcription. Interestingly, the IL-4 induction of immunoglobulin class switching to IgE is increased in splenic B cells from BCL-6 (-/-) mice. Therefore, genes regulated by STAT binding sites may be one class of targets for BCL-6 mediated transcriptional repression.