Molecular and genetic analysis of DP103

描述(由申请人提供)：巨噬细胞与前体细胞的分化伴随着不可逆转的生长停滞，这是由细胞周期相关基因的稳定转录抑制引起的。抑制导致GO停滞的机制在白血病发生中起着核心作用。在巨噬细胞分化过程中上调的有丝分裂原ETS转录抑制因子(Mets)诱导的生长停滞需要死盒蛋白DP103(DP103)。DP103还可以作为其他一些不同转录因子的辅抑制子，这表明DP103作为辅抑制子具有广泛的功能。现建议对DP103的发育功能、转录靶点和抑制机制进行研究。通过在巨噬细胞文库的酵母双杂交筛选中确定新的相互作用伙伴，将评估它作为大量转录因子的辅助抑制物的可能作用。为了评价其在胚胎发育和造血过程中控制增殖的功能，将建立DP103基因敲除小鼠，并分析巨噬细胞和巨噬细胞前体细胞的增殖潜力。最后，将通过全基因组定位分析来分析DP103潜在的表观遗传抑制机制。

DESCRIPTION (provided by applicant): 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.