Control of gene expression during myeloid hematopoietic differentiation is exerted at two distinct levels: first, commitment to myeloid specificity, then temporal regulation of stage-specific genes as mature phagocytes develop from committed progenitors. During cellular differentiation, a battery of genes specific to mature phagocytic cells must be activated. A transcriptional repressor protein, designated CDP, is implicated in the temporal control of phagocyte-specific genes. CDP binds to the promoter of the myeloid-specific cytochrome gene, gp91-phox, only in immature or non-myeloid cells in which gp91-phox is not transcribed. Upon terminal phagocyte differentiation, CDP binding to the gp-91-phox promoter is diminished and transcription is activated. CDP was originally proposed as a """"""""CCAAT Displacement Protein"""""""" which acted by preventing binding of positively acting """"""""CCAAT-box"""""""" binding factors. However, it is now clear that CDP can bind DNA and act as a negative regulator in the absence of a CCAAT site. CDP is also implicated in regulation of another hematopoietic system: butyrate-induced gamma- globin expression in K562 leukemia cells in vitro. To better understand the role which this factor plays in hematopoietic gene expression, we purified the human protein and isolated CDP cDNA clones. We found that CDP gene encodes a homeodomain protein, closely homologous to the Drosophila regulatory protein, cut. In addition to a unique homeodomain, CDP shares with cut three highly conserved peptide sequences designated :Cut repeats"""""""". By analogy to cut, which acts to specify cell fate in several tissues of the developing fly, a working hypothesis is that CDP acts as part of the switch to terminal differentiation in hematopoietic cells. The goal of these studies it to characterize in the mechanism of action of human CDP. The regulatory role of CDP will be assessed in stable transformants of cell lines expressing CDP constitutively. The biosynthesis and cellular metabolism of CDP will be investigated. The basis of loss of CDP DNA-binding activity during differentiation of HL60 myeloid leukemia cells will be determined. As CDP is a ubiquitous protein rather than a tissue-specific regulatory switch, understanding its role in controlling temporal gene expression in myeloid cells will be broadly relevant to the mechanism of genetic control in differentiation of other hematopoietic lineages and in other tissue types. Elucidation of the normal mechanism of genetic control of phagocyte-specific gene expression during differentiation will lead to better understanding of diseases in which myeloid differentiation is abnormal, including Kostmann syndrome (congenital neutropenia) and acute and chronic myelogenous leukemias.
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