Function of MEF in Hematopoietic Cells

Project: Research project

Project Details

Description

The goal of this proposal is to further characterize the functional activities of MEF, a member of the ETS
family of transcription factors, in hematopoietic cells. We have learned a great deal about the function of
MEF, having identified its essential role in innate immunity and in regulating hematopoietic stem cell
quiescence. Our focus now is to more completely define the role of MEF in controlling normal (and
leukemic) hematopoietic stem cell behavior, characterize the cell type specificity of its transforming
properties, and understand the mechanistic basis for its growth promoting effects. To accomplish this, we
propose to further define the role of MEF in regulating hematopoietic stem cell (HSC) quiescence and the
chemo-sensitivity and radio-sensitivity of hematopoietic cells, by modulating MEF levels in HSCs ( by both
overexpressing MEF and reducing the level of MEF using siRNA). We will also define the role that changes
in cyclin C expression (or cyclin D2 or D3) play in the regulation of quiescence by MEF, and will define how
known cell cycle regulatory genes, such as p21, modulate the effects of MEF on HSC behavior. We will also
further define the role of MEF in malignant transformation by defining the importance of MEF in the
transforming properties of known oncogenes (such as H-RasV12) using mouse embryonic fibroblasts, and
by determining how changes in MEF levels cooperate or antagonize the ability of leukemia-associated
oncogenes such as BCR-ABL, NUP98-HOXA9, and NUP98-HOXD13 to transform hematopoietic cells. We
will also define the role MEF plays in regulating p53 dependent processes in the cell by carefully defining
the phenotype of MEF null, p53 null double knock-out mice. To define the mechanisms underlying these
effects of MEF on cell behavior, we will determine how phosphorylation of MEF by cellular kinases (e.g. the
ERK2 MAP kinase) affects the function of MEF in a variety of biological assays, and will utilize transcript
profiling to further define which MEF target genes are essential for its effects on cellular quiescence, growth,
and transformation. These studies will provide valuable insight into the transcriptional regulation of normal
and leukemic hematopoietic stem cell quiescence, and cellular transformation, which are key issues in stem
cell biology and the pathogenesis of human cancer.
StatusFinished
Effective start/end date7/15/076/30/08

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases: $500,000.00

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