CCAAT Enhancing Binding Protein Alpha (C/EBP Alpha) is a transcription factor which is absolutely necessary for development of mature neutrophils. In addition, C/EBP Alpha is necessary for expression of the G-CSF receptor in hematopoietic cells. However, the mechanism by which C/EBP alpha is up regulated and activated by extracellular signals has not been elucidated. Signaling by factors such as G-CSF and the proto-oncogene Ras play important roles in both normal myeloid development and in acute myelogenous leukemia, in which differentiation of myeloid blasts is blocked. The broad goal of this proposal is to investigate how these signals, particularly those mediated by G-CSF and Ras, serve to augment the ability of C/EBP Alpha to stimulate expression of its target genes, including the G-CSF receptor itself. Our hypothesis is that these signaling mechanisms play key roles in the differentiation of myeloid cells from multi-potential progenitors, a process which is interrupted in myeloid leukemia. By studying normal signaling processes in myeloid commitment, we aim to understand the abnormalities in leukemia. Studies by ourselves and others have shown that the function of C/EBP Alpha, as well as the signaling pathways mediated by the G-CSF receptor and Ras, are essential steps in granulocytic development.
Our specific aims are to delineate the critical role of the pathways signally C/EBP Alpha in myeloid development: (1) To determine the mechanisms by which Ras activates the ability of C/EBP Alpha to regulate the expression of genes important for myeloid development. (2) To determine the upstream signals pathways of C/EBP Alpha expression and activity. (3) To determine the result of expression of specific C/EBP Alpha wild type and mutant proteins, as well as G-CSF receptor constructs, in cell lines and C/EBP Alpha mutant mice. These experiments will be greatly enhanced by the interactions with other members of this program, particularly with respect to investigating signal transduction pathways in myelopoiesis.
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