Associate Provost for Research Boston University Medical Campus
NCI - National Cancer Institute	Research Resources

Abstract

Abstract: DESCRIPTION (provided by applicant): 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.

Thesaurus Terms:
B cell lymphoma, Hodgkin's disease, carcinogenesis, neoplastic transformation, oncogene, protein structure function, transcription factor
apoptosis, chimeric protein, disease /disorder model, estrogen receptor, fibroblast, gene mutation, inhibitor /antagonist, model design /development, neoplasm /cancer genetics, nuclear factor kappa beta, oncoprotein, protein protein interaction, small molecule
chicken, laboratory mouse, reporter gene, tissue /cell culture, yeast

Institution:	BOSTON UNIVERSITY
	881 COMMONWEALTH AVENUE
	BOSTON, MA 02215
Fiscal Year:	2006
Department:	BIOLOGY
Project Start:	01-SEP-1988
Project End:	31-MAY-2009
ICD:	NATIONAL CANCER INSTITUTE
IRG:	CAMP