Differentiation of macrophages from precursor cells is accompanied by irreversible growth arrest, induced by stable transcriptional repression of cell cycle-associated genes. Inhibition of the mechanisms that cause GO arrest plays a central role in leukemogenesis. Growth arrest induced by mitogenic ets transcriptional suppressor (METS), which is upregulated during macrophage differentiation requires the DEAD box protein DP103 (DP103). DP103 also acts as a corepressor for a number of other, divergent transcription factors, which suggests a broad functional role for DP103 as a corepressor. Studies are proposed to define the developmental functions, transcriptional targets and repression mechanisms of DP103. Its possible role as a corepressor for a larger number of transcription factors will be assessed by identifying new interaction partners in a yeast two-hybrid screen of a macrophage cDNA library. To assess its function in embryonic development, in controlling proliferation during hematopoiesis, DP103 knockout mice will be generated and the proliferative potential of macrophages and macrophage precursors analyzed. Finally, the potentially epigenetic repression mechanism of DP103 will be analyzed by genome-wide location analysis. ? ?
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