The focus of this renewal application continues to be on the molecular basis of hematopoiesis. Specifically, we are interested in the role of proto-oncogenes and immediate early response genes m leukemic cell differentiation and cell cycle progression. During the previous granting period, we established that several such genes (c-myc, c-myb, and jun family members) are intimately involved in these processes. In the continuation of this work, we will study the contributions that protein:protein and protein:DNA interactions make to these events. In keeping with our long-standing interest in the c-myc oncoprotein, we will begin to explore, both in vitro as well as in transgenic animals, the molecular and biological consequences of its interaction with the recently described max proteins. Point mutations will be used to define those amino acid residues critical to the overall function and specificity of the c-myc DNA binding domain Finally, we will utilize bacterially expressed """"""""Id"""""""" protein, a known negative regulator of """"""""helix-loop-helix"""""""" proteins, as an affinity reagent to purify and clone positive regulators of erythroleukemic differentiation. The above studies will thus expand and refine our current notions of the roles of oncoproteins in erythroleukemic differentiation and may uncover novel pathways leading to these events.
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