Inflammation is a genetically programmed response to cellular stress that can be activated by a number of mechanisms, including induction of transcription of critical genes. NF-κB is a highly conserved transcription factor that plays a pivotal role in the transcriptional activation of this stress response and has been intimately linked to a range of human maladies including autoimmune disorders and cancer. Therefore, the regulation of this transcription factor is of critical importance for normal physiology and disease. In particular, deregulated NF-κB function plays a role in chronic inflammatory disorders such as inflammatory bowel disease, and the potential of these diseases to progress towards cancer.
Our laboratory is focused on the molecular regulation of the inflammatory response, particularly in the intestinal tract, and the various events that control the pro-inflammatory transcription factor NF-κB . Our work has identified specific pathways for the termination of NF-κB mediated transcription that involve the ubiquitination and proteasomal degradation of this transcription factor.
Termination of NF-κB dependent transcription
We have identified that ubiquitin-mediated termination of NF-κB dependent transcription involves a ubiquitin ligase complex that contains COMMD1 as an essential cofactor. This protein is recruited to gene promoter sites where it facilitates the release of chromatin-bound NF-κB subunits by promoting their ubiquitination.
With support from the NIH (R01 DK073639), we are utilizing mouse models of Commd1 deficiency to study the contribution of this gene to sepsis and acute inflammation in vivo. Moreover, we are evaluating the mechanism by which COMMD1 is recruited to promoter sites in the first place, and the roles of various post-translational modifications of NF-κB subunits in their ubiquitination by the COMMD1-containing complex. In addition, with the support of the Crohn’s and Colitis Foundation of America (CCFA SRA 2737) we have been examining the role of this gene in intestinal inflammation and inflammatory bowel disease pathogenesis.
Developing themes within this field of research are the identification of additional co-factors involved in this process, some of which are emerging in parallel human genetic studies, as well as a detailed examination of the temporal and sub-cellular organization of this pathway, which are disclosing surprising features in this ubiquitination cascade.
Other cellular functions of COMMD Proteins
COMMD1 is the founding member of a family of 10 conserved factors present in most eukaryotic organisms. At the present time, very little is known about the functions of other family members, and we have a long-standing interest in identifying cellular functions for these factors and defining common molecular mechanisms of action for these molecules.
These studies have identified that besides its role in the NF-κB pathway, COMMD1 can regulate other critical cellular pathways. In particular, we have defined a role for this factor as a negative regulator of the hypoxia inducible factor (HIF), a transcriptional master regulator of the hypoxic response. As such, COMMD1 is involved in critical processes linked to HIF, such as tumor adaptation to hypoxia and the control of local invasion and metastasis. In the future, we are interested in using animal models to better define if COMMD1 can be a targetable molecule for the treatment of invasive cancer.
In addition, we have been investigating whether other COMMD family members play non-redundant roles in cellular and developmental physiology. These studies rely on deficient mouse lines and proteomic profiling and have disclosed unique functions for the Commd9 and Commd10 genes in mice. We are continuing to explore their specific functions and mechanisms of action in order to ascertain general mechanisms by which these factors might regulate cellular pathways.