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Brian A. Lewis, Ph.D.

Portait Photo of Brian Lewis
Lymphoid Malignancies Branch
Investigator
Center for Cancer Research
National Cancer Institute
Building 10, Room 6B05
Bethesda, MD 20892
Phone:  
301-435-8323
Fax:  
301-496-9956
E-Mail:  
lewisbri@mail.nih.gov

Biography

Visiting Scientist, NCI, NIH 2006-2008

Research Assistant Professor/Senior Fellow 2000-2006
UMDNJ, Department of Biochemistry

Postdoctoral Fellow 1993-2000 Children's Hospital,
Harvard Medical School

Ph.D. 1993 Molecular Biology, Princeton University

B.A. 1988 University of Virginia

Research

My lab is a new addition to the Metabolism Branch/CCR/NCI and will focus on understanding transcriptional initiation largely through protein biochemistry using functional cell-free systems. In addition, the lab will be exploiting ChIP, ChIP-seq, and shRNA techniques, which are powerful additions to the biochemist's arsenal in establishing the in vivo relevance of the cell-free systems. There are two projects in the lab that address specific problems in eukaryotic transcriptional regulation.

The first project in the lab examines the transcriptional biology of the REL family members of NF-kB. The three REL proteins supply the transactivation functions in the NF-kB family. We have analyzed the functional requirements of REL members in several B-cell lymphomas. Although it has been clear for some time that these lymphomas are NF-kB-dependent, it has never been clear what role each REL family member plays in a lymphoma phenotype. We have shown that Hodgkin lymphoma (HL) uniquely requires relB. We did not find this requirement in any other B-cell lymphoma we studied. Secondly, we also found that primary HL tumors contain activated noncanonical NF-kB pathways, which is necessary for the nuclear translocation of relB. We have also found that a drug inhibitor of this pathway is specifically killing HL cell lines and not any other B-cell lymphoma line. We are currently exploring this dependency on the noncanonical pathway further with biochemical, ChIP-seq, and microarray analyses of both HL and non-Hodgkin B-cell lymphomas. These studies are revealing important differences between HL and NHL in terms of their NF-kB-regulated gene networks. This work will allow us to create network-based definitions of these B-cell lymphomas. Coupled with our drug inhibitor and studies of the noncanonical pathway, these studies will increase our understanding of and therapeutic interventions in lymphoma biology.

Our second project also combines the expertise of the lab in both in vivo biology and in vitro functional biochemistry. We have defined a new functional form of human RNA polymerase II. This species of pol II is defined by O-GlcNAc modifications of the C-terminal domain of pol II (CTD). In contrast to the phosphorylated species of pol II, which is involved in post-transcriptional processes such as RNA processing and termination of transcription, the O-GlcNAc modification of the CTD defines a pre-initiation species of pol II. Our data now suggests that there is a cycle of glcnacylation and de-glcnacylation on RNA pol II and that this cycle is necessary for assembly of a functional preinitiation complex at the promoter. We are exploring this further with in vivo assays such as shRNA, ChIP-seq, and microarray experiments to determine the in vivo ramifications of these events. In addition, we are now reconstituting O-GlcNAc-dependent transcription systems in vitro in order to precisely define the mechanisms of O-GlcNAc-dependent regulation of RNA pol II.

This page was last updated on 6/7/2013.