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-k proteins in the onset and progression of hematopoietic and solid tumors. Proteins in the Rel/NF B-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-kB activity to human cancer has emerged in recent years, consistent with the acute oncogenicity of the Rel/NF-B oncoprotein v-Rel in inducing fatal leukemia/lymphomas in animal models. Aberrant Rel/NF-kB activity is found in many human leukemias, lymphomas, myelomas and Hodgkin's disease. Chromosomal amplification, rearrangement, overexpression and/or constitutive activation of the rel and nf- B genes are also observed in breast, colon, lung and ovarian cancer. The viral and cellular Rel proteins thus provide a good model system to study how Rel/NF-kB functions in normal lymphoid cells and to understand how its aberrant activity leads to malignancy. Our research focuses on the functional domains and regulation of the Rel/NF-kB factors, and on their role in cell growth, survival and transformation. Ongoing studies focus on the transcriptional activity and regulation of the Rel/NF-kB factors, on their role in cell proliferation. apoptosis and oncogenesis, and on the cellular genes that they control. This comprehensive approach will help to clarify the mechanism by which Rel/NF-kB proteins function in the immune system and in leukemia/lymphomagenesis. In addition, since Rel/NF-kB activity has been implicated in several other disease conditions including acute inflammatory disorders, the systematic analysis of Rel/NFk regulation and relevant target genes may also provide important insights into novel approaches for therapeutic intervention.
Selected Publications
Medina D, Goodell L, Glod J, Gelinas C, Rabson A, Strair R. (2012) Feb 27. [Epub ahead of print]Mesenchymal stromal cells protect mantle cell lymphoma cells from spontaneous and drug-induced apoptosis through secretion of B-cell activating factor and activation of the canonical and non-canonical nuclear factor κB pathways. Haematologica.
Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli-Uzunbas G, Kamphorst JJ, Chen G, Lemons JM, Karantza V, Coller HA, Dipaola RS, Gelinas C, Rabinowitz JD, White E. (2011) Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev. Mar 1;25(5):460-70.
Fan G, Simmons MJ, Ge S, Dutta-Simmons J, Kucharczak J, Ron Y, Weissmann D, Chen CC, Mukherjee C, White E, Gélinas C. (2010) Defective ubiquitin-mediated degradation of antiapoptotic Bfl-1 predisposes to lymphoma. Blood. Apr 29;115(17):3559-69.
Drawid A, Gupta N, Nagaraj VH, Gélinas C, Sengupta AM. (2009) OHMM: a Hidden Markov Model accurately predicting the occupancy of a transcription factor with a self-overlapping binding motif. BMC Bioinformatics. 10:208.
Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY, Bray K, Reddy A, Bhanot G, Gelinas C, Dipaola RS, Karantza-Wadsworth V, White E. (2009) Autophagy suppresses tumorigenesis through elimination of p62. Cell. 137(6):1062-75.
Fan G, Fan Y, Gupta N, Matsuura I, Liu F, Zhou XZ, Lu KP, Gélinas C. (2009) Peptidyl-Prolyl Isomerase Pin1 Markedly Enhances the Oncogenic Activity of the Rel Proteins in the Nuclear Factor-{kappa}B Family. Cancer Res. 69(11):4589-97.
Dutta J, Fan G, Gélinas C. (2008) CAPERalpha is a novel Rel-TAD-interacting factor that inhibits lymphocyte transformation by the potent Rel/NF-kappaB oncoprotein v-Rel. J Virol. 82(21):10792-802.
Simmons, M.J, Fan G, Zong, W.X., Degenhardt K, White E and Gelinas C. (2008) Bfl-1/A1 functions, similar to Mcl-1, as a selective tBid and Bak antagonist. Oncogene 27: 1421-1428.
Gupta N, Delrow J, Drawid, A., Sengupta A, Fan G and Gelinas C. (2008) Repression of BLNK and BCAP is important for lymphocyte transformation by Rel proteins. Cancer Res. 68: 808-814.
Fan, Y, Dutta J, Gupta N, Fan G and Gelinas C. (2007) Regulation of programmed cell death by NF-kB and its role in tumorigenesis and therapy, in Programmed Cell Death in Cancer Progression and Therapy, R. Khosravi-Far and E. White eds. Springer: The Netherlands, pp 217-244.
Fan Y and Gelinas 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.
Dutta J, Fan, Y, Gupta N, Fan G and Gelinas C. (2006) Current insights into the regulation of programmed cell death by NF-kB. Oncogene 25: 6800-6816.
Pegman, P.M., Smith, S.M., D'Souza, B.N., Loughran, S.T., Maier, S, Kempkes, B., Cahill, P.A., Simmons, M.J., Gelinas, C. and Walls, D.. (2006) The Epstein-Barr virus nuclear antigen 2 trans-activates the cellular anti-apoptotic bfl-1 gene by a CBF-1/RBPJk dependent pathway. J. Virol. 80: 8133-8144.
Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson A, Chen G, Mukherjee C, Shi Y, Gelinas C, Fan Y, Nelson D, Jin S and White E. (2006) Autophagy promotes tumor cell survival and restricts necrosis, inflammation and tumorigenesis. Cancer Cell 10: 51-64.
Fan Y, Dutta J, Gupta N, Gelinas C. (2006) Molecular Basis of Oncogenesis by NF-kB: From a bird¹s eye view to a relevant role in cancer. In: Liou H-C, ed. in NF-kB/Rel Transcription Factor Family. Georgetown: Landes Bioscience, New York: Springer Science+Business Media,pp 112-130.
Kucharczak, J.F., Simmons, M.J., Duckett, C.S. and Gelinas, C. (2005) Constitutive proteasome-mediated turnover of Bfl-1/A1 and its processing in response to TNF receptor activation in FL5.12 pro-B cells convert it into a pro-death factor. Cell Death & Differ. 12: 1225-1239.
Xu C, Shen G, Chen C, Gelinas C and Kong ANT. (2005) Suppression of NF-kB and NF-kB-regulated gene expression by sulforaphane and PEITC through IkBa, IKK pathway in human prostate cancer PC-3 cells. Oncogene 24: 4486-4495.
Gelinas, C. and White, E. (2005) BH3-only proteins in control: specificity regulates MCL-1 and BAK-mediated apoptosis. Genes & Dev. 19: 1263-1268.
Fan,Y., Rayet, B. and Gelinas, C. (2004) Divergent C-terminal transactivation domains of Rel/NF-kB proteins are critical determinants of their oncogenic potential. Oncogene 23: 1030-1042.
D’Souza, B.N., Edelstein, L.C., Pegman, P.M., Smith, S.M., Loughran, S.T., Clarke, A., Mehl, A., Rowe, M., Gelinas, C., and Walls, D. (2004) Nuclear factor kB-dependent activation of the anti-apoptotic bfl-1 gene by the Epstein-Barr virus (EBV) latent membrane protein 1 and activated CD40 receptor. J. Virol. 78: 1800-1816.
