Department of Biochemistry and Molecular Biology
Robert Wood Johnson Medical School
Cancer Institute of New Jersey
Ph.D., 1985, Université de Sherbrooke
Telephone: (732) 235-5035
Fax: (732) 235-4466
Rel, NF-κβ, cancer, transcription, apoptosis, proliferation, leukemia, lymphoma, oncogene, transformation
Cancer arises when the delicate balance between cell proliferation and cell death is perturbed. Signals that promote uncontrolled cell division, and those that block cell death, drive the development and progression of tumors. Our laboratory has a long-standing interest in the role of the Rel/NF-κβ proteins in the onset and the progression of hematopoietic and solid tumors.
Proteins in the Rel/NF-κβ-family of transcription factors play fundamental roles in immune and inflammatory responses, and are implicated in the control of cell proliferation, the inhibition of apoptosis and in oncogenesis. Experimental evidence linking deregulated Rel/NF-κβ activity to human cancer has emerged in recent years, consistent with the acute oncogenicity of the Rel/NF-κβ oncoprotein v-Rel in inducing fatal leukemia/lymphomas in animal models. As many as 10% of human B- and T-cell cancers can show alterations in the genes coding for the Rel/NF-κβ proteins or their regulator Iκβa. As such, constitutive Rel/NF-κβ activity is found in a variety of human leukemias, lymphomas, myelomas and Hodgkins disease. Chromosomal amplification, rearrangement, overexpression and/or constitutive activation of the Rel and NF-κβ genes is also observed in breast, colon, lung, ovarian and prostate cancer. It is therefore important to clarify how these proteins function in normal and in cancer cells. The viral and cellular Rel proteins thus provide an excellent and unique model system to decipher how cellular Rel/NF-κβ factors function in normal lymphoid cells and to understand how their aberrant activities lead to malignancy.
Our research focuses on the functional domains and the regulation of the Rel/NF-κβ proteins and on their role in cell growth, survival and transformation. Ongoing studies focus on the DNA-binding and transcriptional activities of the Rel proteins, their regulation by Iκβ factors, their role in apoptosis, cell proliferation and lymphoid cell transformation, as well as on the cellular genes that they control. These include the cell death inhibitor Bfl-1/A1 that we recently identified as a direct transcriptional target of NF-κβ and TAPIR, a new inhibitor of the NF-κβ signaling pathway.
This comprehensive approach will help to clarify the mechanism by which Rel/NF-κβ proteins function in the immune system and in oncogenesis. In addition, since Rel/NF-κβ activity is implicated in many disease conditions ranging from acute inflammatory conditions to cancer, the systematic analysis of its regulation and relevant target genes may provide important insights into novel approaches for therapeutic intervention.
The cell death inhibitor Bfl-1/A1 is a Rel/NF-κβ target that suppresses TNFa-induced cytochrome c release and apoptosis. Human MCF-7 breast cancer cells were transfected with GFP-tagged Bfl-1. After treatment with TNFa, cells were immunostained for cytochrome c localization and analyzed by fluorescent microscopy. Cytochrome c is retained in the mitochondria of GFP-Bfl-1-expressing cells following TNFa treatment, but it is released in cells that do not express GFP-Bfl-1.
Fan, Y, Dutta J, Gupta N, Fan G and Gélinas C. (2008) Regulation of programmed cell death by NF-κβ and its role in tumorigenesis and therapy. Adv Exp Med Biol. 615:223-50.
Gupta N, Delrow J, Drawid, A., Sengupta AM, Fan G and Gélinas C. (2008) Repression of B-cell linker (BLNK) and B-cell adaptor for phosphoinositide 3-kinase (BCAP) is important for lymphocyte transformation by Rel proteins. Cancer Res. 2008 Feb 1;68(3):808-14.
Simmons, M.J, Fan G, Zong, W.X., Degenhardt K, White E and Gélinas C. (2008) Bfl-1/A1 functions, similar to Mcl-1, as a selective tBid and Bak antagonist. Oncogene 27:1421-8
Fan Y, Gélinas C. (2007) An optimal range of transcription potency is necessary for efficient cell transformation by c-Rel to ensure optimal nuclear localization and gene-specific activation. Oncogene 26:4038-4043