The Ets proteins, and other transcription factors which interact with Ets proteins, play a critical role in development of nearly every hematopoietic lineage, and are directly involved in the pathogenesis of many types of experimental and human leukemia. The overall goal of this program is to study specific members of this family in order to understand this essential role in normal hematopoiesis, and how abnormalities in structure and/or function of this class of proteins lead to leukemia. The future aims are to use this knowledge to design specific therapies for treatment of hematopoietic malignancies. The specific projects will include the following proposals: (1) C/EBP alpha signal transduction and myelopoiesis; (2) Function of ELF1 and a novel Ets factor NERF in beta cells; (3) Characterization of TEL, a new leukemogenic Ets protein; (4) The role of AML 1 in myeloid development and leukemia; (5) Structure and function of Ets/bZIP protein-DNA complexes; (6) MAP kinase regulation of TCF proteins. The administrative core shall be responsible for many interactive functions of the program, including regular studies of transcriptional regulation, protein-protein interactions, phosphorylation and signal transduction, knockout and knocking mice, and structure-function relationships, we will provide new information concerning a very interesting group of proteins whose functions and interactions are directly related to hematopoiesis and leukemogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA072009-05
Application #
6376303
Study Section
Subcommittee G - Education (NCI)
Project Start
1997-09-15
Project End
2003-04-30
Budget Start
2001-07-06
Budget End
2003-04-30
Support Year
5
Fiscal Year
2001
Total Cost
$1,401,749
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
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

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