The Rel/NF-kappaB family of transcription factors is mis-regulated in a number of human cancers, and this proposal focuses on systems that model this signaling pathway in cancer. In particular, the human REL gene (encoding c-Rel or REL) is amplified or mutated in several rather common human lymphoid cell cancers, especially diffuse B-cell lymphomas and Hodgkin's lymphoma. Nevertheless, there are few in vitro models for REL-induced lymphomagenesis, and there are no specific inhibitors of REL protein function. Thus, one primary focus of this proposal is to use a model system developed in this laboratory to further understand the mechanism by which human REL malignantly transforms chicken lymphoid cells by identifying REL mutants with altered transforming activity and proteins that can interact with REL transactivation sequences required for transformation. Furthermore, using fusion proteins and co-expression systems, the inhibition of REL-induced transformation by the human estrogen receptor will be investigated and REL target genes will be identified. In two related Aims, attempts will be made to develop mouse model systems for REL-induced oncogenesis, and in collaborative studies with Dr John A Porco (Chemistry Department and Center for Chemical Methodology & Library Development at Boston University), first-stage chemical inhibitors of REL protein function will be developed using a yeast-based reporter gene assay. Finally, mouse cell lines in which the absence of RelA is associated with the transformed state will be further characterized. As such, this proposal describes exploratory research that seeks to develop models to validate the REL transcription factor as a therapeutic target in certain human lymphoid cell cancers, and, as such, the information derived from this work may have prognostic or therapeutic significance for the treatment of specific human diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA047763-17
Application #
6822490
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Cole, John S
Project Start
1988-09-01
Project End
2009-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
17
Fiscal Year
2004
Total Cost
$313,310
Indirect Cost
Name
Boston University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
02215
Haery, Leila; Mussakhan, Sultan; Waxman, David J et al. (2016) Evidence for an oncogenic modifier role for mutant histone acetyltransferases in diffuse large B-cell lymphoma. Leuk Lymphoma 57:2661-71
Gilmore, Thomas D; Gélinas, Céline (2015) Methods for assessing the in vitro transforming activity of NF-?B transcription factor c-Rel and related proteins. Methods Mol Biol 1280:427-46
Haery, Leila; Lugo-Picó, Julián G; Henry, Ryan A et al. (2014) Histone acetyltransferase-deficient p300 mutants in diffuse large B cell lymphoma have altered transcriptional regulatory activities and are required for optimal cell growth. Mol Cancer 13:29
Thompson, Ryan C; Vardinogiannis, Iosif; Gilmore, Thomas D (2013) Identification of an NF-?B p50/p65-responsive site in the human MIR155HG promoter. BMC Mol Biol 14:24
Thompson, Ryan C; Vardinogiannis, Iosif; Gilmore, Thomas D (2013) The sensitivity of diffuse large B-cell lymphoma cell lines to histone deacetylase inhibitor-induced apoptosis is modulated by BCL-2 family protein activity. PLoS One 8:e62822
Yeo, Alan T; Porco Jr, John A; Gilmore, Thomas D (2012) Bcl-XL, but not Bcl-2, can protect human B-lymphoma cell lines from parthenolide-induced apoptosis. Cancer Lett 318:53-60
Wolenski, Francis S; Chandani, Sushil; Stefanik, Derek J et al. (2011) Two polymorphic residues account for the differences in DNA binding and transcriptional activation by NF-?B proteins encoded by naturally occurring alleles in Nematostella vectensis. J Mol Evol 73:325-36
Wolenski, Francis S; Garbati, Michael R; Lubinski, Tristan J et al. (2011) Characterization of the core elements of the NF-?B signaling pathway of the sea anemone Nematostella vectensis. Mol Cell Biol 31:1076-87
Garbati, Michael R; Thompson, Ryan C; Haery, Leila et al. (2011) A rearranged EP300 gene in the human B-cell lymphoma cell line RC-K8 encodes a disabled transcriptional co-activator that contributes to cell growth and oncogenicity. Cancer Lett 302:76-83
Gilmore, Thomas D; Garbati, Michael R (2011) Inhibition of NF-?B signaling as a strategy in disease therapy. Curr Top Microbiol Immunol 349:245-63

Showing the most recent 10 out of 19 publications