Abstract

Our goal is to understand how embryonic pluripotent cells differentiate into specific cell types of the immune system and to identify developmental defects leading to leukemia and lymphoma formation. Our approach is to analyze transcriptional control mechanisms for developmentally regulated beta cell-specific gene and isolated a novel Ets factor, NERF, with three alternative splice forms form human spleen and fetal liver. NERF is closely related to ELF-1, and Ets factor linked to T cell-specific gene expression; however, our preliminary results indicate that ELF-1 is a major Beta cell nuclear factor which interacts with the activates regulatory elements in Beta cell-specific genes. NERF and ELF-1 are highly expressed in early stages of Beta cell development and bind with similar affinity to Ets sites in several Beta cell-specific genes the highest affinity is for the Beta cell tyrosine kinase genes, lyn & blk. We propose to investigate the role and mechanism of action of NERF and ELF-1 in regulating Beta cell-specific genes using the blk gene as one apparent target gene.
Our aim i s to evaluate the role of NERF in Beta cell development and analyze structure/function relationships of NERF and ELF-1 to understand mechanisms responsible for functional differences between these two factors. Thus, the specific aims are to:
Specific AIM number 1. Determine the role of NERF and ELF-1 in the regulation of Beta cell specific blk gene expression.
Specific Aim number 2. Determine the role of protein-protein interactions and phosphorylation in the function of ELF-1 or NERF.
Specific Aim number 3. Determine the effect of targeted disruption of the NERF gene on Beta cell development and blk gene expression. Due to the importance of the Ets family in regulation of various tissue- and differentiation-specific genes, in general, and hematopoiesis, in particular, NERF and ELF-1 are expected to play a central role in Beta cell development. Elucidation of the function NERF and ELF-1 in regulating Beta cell development will provide exciting opportunities to test the hypothesis that altered functions of these Ets factor result in leukemia.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA072009-04
Application #
6353495
Study Section
Project Start
2000-09-18
Project End
2001-06-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
4
Fiscal Year
2000
Total Cost
$348,824
Indirect Cost

  Institution

Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215

  Publications

Arinobu, Yojiro; Mizuno, Shin-ichi; Chong, Yong et al. (2007) Reciprocal activation of GATA-1 and PU.1 marks initial specification of hematopoietic stem cells into myeloerythroid and myelolymphoid lineages. Cell Stem Cell 1:416-27
Radomska, Hanna S; Basseres, Daniela S; Zheng, Rui et al. (2006) Block of C/EBP alpha function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations. J Exp Med 203:371-81
Iwasaki, Hiromi; Mizuno, Shin-ichi; Arinobu, Yojiro et al. (2006) The order of expression of transcription factors directs hierarchical specification of hematopoietic lineages. Genes Dev 20:3010-21
Peterson, Luke F; Boyapati, Anita; Ranganathan, Velvizhi et al. (2005) The hematopoietic transcription factor AML1 (RUNX1) is negatively regulated by the cell cycle protein cyclin D3. Mol Cell Biol 25:10205-19
Opferman, Joseph T; Iwasaki, Hiromi; Ong, Christy C et al. (2005) Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells. Science 307:1101-4
Biggs, Joseph R; Zhang, Youhong; Peterson, Luke F et al. (2005) Phosphorylation of AML1/RUNX1 regulates its degradation and nuclear matrix association. Mol Cancer Res 3:391-401
Iwasaki, Hiromi; Somoza, Chamorro; Shigematsu, Hirokazu et al. (2005) Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation. Blood 106:1590-600
Koschmieder, Steffen; Rosenbauer, Frank; Steidl, Ulrich et al. (2005) Role of transcription factors C/EBPalpha and PU.1 in normal hematopoiesis and leukemia. Int J Hematol 81:368-77
Zhang, Pu; Iwasaki-Arai, Junko; Iwasaki, Hiromi et al. (2004) Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBP alpha. Immunity 21:853-63
Ross, Sarah E; Radomska, Hanna S; Wu, Bo et al. (2004) Phosphorylation of C/EBPalpha inhibits granulopoiesis. Mol Cell Biol 24:675-86

Showing the most recent 10 out of 52 publications