): Normal function of the immune system requires the differentiation of pluripotent stem cells into mature lymphoid cells. Abnormalities in this process can lead to the development of leukemias and lymphomas. The differentiation and proliferation of cells of the immune system often occur in response to external stimuli, such as antigens or growth substances. This response requires that the receptors on the surface of these cells recognize the stimulus and initiate a series of signal transduction events. These signals are necessary for both developmental decisions and initiation of immune responses by B and T lymphocytes. One approach for analyzing the regulation of the immune system is to isolate transcription factors which regulate B cell specific genes. In particular, the investigators recently identified a novel member of the Ets transcription factor/oncogene family, NERF, from human spleen and fetal liver, which has a DNA binding domain which is highly homologous to the Ets factor ELF-1. ELF-1 has been implicated in the regulation of T cell-specific gene expression. The preliminary data demonstrate that NERF and ELF-1 are highly expressed in B cells and interact with the same regulatory elements of a whole set of B cell-specific genes including blk, lyn, TdT, mb-1, B29 and the Igh pi site. Many of these genes are differentially regulated during B cell development. Furthermore, disruption of the function of some of the transcription factors which regulate the expression of these genes such as BSAP and EBF results in marked abnormalities in B cell differentiation and function. NERF and ELF-1 appear to have the highest binding affinity for the promoter regions of the lyn and blk tyrosine kinase genes. Both lyn and blk are required for normal signal transduction of the activated antigen/receptor complex on B lymphocytes. The hypothesis for the proposed studies is that, because NERF and ELF-1 bind with high affinity to the regulatory regions in the promoters of a number of B cell specific genes, they are critical for B cell function and differentiation. They may have opposing effects, one upregulating gene expression and the other downregulating it. They may be redundant and have similar effects; or one may be more active than the other in certain cell types or at certain development stages. To further elucidate the role of ELF-1 and NERF in B cell development and function the goals of this project are to determine their expression at different stages of B cell development, demonstrate their ability to function as transcription factors in regulating B cell specific genes, and determine the effect on immune system function and development when these genes are disrupted.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA071429-04
Application #
2895587
Study Section
Cancer Research Manpower and Education Review Committee (CRME)
Program Officer
Myrick, Dorkina C
Project Start
1996-09-01
Project End
2001-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
Grall, Franck T; Prall, Wolf C; Wei, Wanjiang et al. (2005) The Ets transcription factor ESE-1 mediates induction of the COX-2 gene by LPS in monocytes. FEBS J 272:1676-87
Grall, Franck; Gu, Xuesong; Tan, Lujian et al. (2003) Responses to the proinflammatory cytokines interleukin-1 and tumor necrosis factor alpha in cells derived from rheumatoid synovium and other joint tissues involve nuclear factor kappaB-mediated induction of the Ets transcription factor ESE-1. Arthritis Rheum 48:1249-60
Dube, A; Thai, S; Gaspar, J et al. (2001) Elf-1 is a transcriptional regulator of the Tie2 gene during vascular development. Circ Res 88:237-44
Rudders, S; Gaspar, J; Madore, R et al. (2001) ESE-1 is a novel transcriptional mediator of inflammation that interacts with NF-kappa B to regulate the inducible nitric-oxide synthase gene. J Biol Chem 276:3302-9
Oettgen, P; Finger, E; Sun, Z et al. (2000) PDEF, a novel prostate epithelium-specific ets transcription factor, interacts with the androgen receptor and activates prostate-specific antigen gene expression. J Biol Chem 275:1216-25
Kas, K; Finger, E; Grall, F et al. (2000) ESE-3, a novel member of an epithelium-specific ets transcription factor subfamily, demonstrates different target gene specificity from ESE-1. J Biol Chem 275:2986-98
Oettgen, P; Kas, K; Dube, A et al. (1999) Characterization of ESE-2, a novel ESE-1-related Ets transcription factor that is restricted to glandular epithelium and differentiated keratinocytes. J Biol Chem 274:29439-52
Dube, A; Akbarali, Y; Sato, T N et al. (1999) Role of the Ets transcription factors in the regulation of the vascular-specific Tie2 gene. Circ Res 84:1177-85
Oettgen, P; Barcinski, M; Boltax, J et al. (1999) Genomic organization of the human ELF3 (ESE-1/ESX) gene, a member of the Ets transcription factor family, and identification of a functional promoter. Genomics 55:358-62
Iljin, K; Dube, A; Kontusaari, S et al. (1999) Role of ets factors in the activity and endothelial cell specificity of the mouse Tie gene promoter. FASEB J 13:377-86

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