Gene Regulation In The Immune System

Child Health And Human Development

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Abstract

This section works on ICSBP (also IRF-8), an immune system specific member of the IRF family. ICSBP is a ~55 kD nuclear protein expressed in macrophages in response to interferon (IFN)-gamma and bacterial lipopolysaccharides (LPS). ICSBP-/- mice display a syndrome similar to chronic myelogenous leukemia (CML) with abnormal expansion of granulocytes. They are also immunodeficient with defective functions. CML is a malignancy of myeloid progenitor cells that is caused by a c-abl-BCR fusion protein created by chromosomal translocation. In order to investigate the role for ICSBP in the CML, we have introduced the ICSBP gene into ICSBP-/- bone marrow myeloid progenitor cells by means of a MSCV retrovirus vector. ICSBP transduction led to macrophage differentiation that accompanied induction of cytokine production and phagocytosis. These cells ceased to divide and expressed a number of macrophage specific genes, and repressed granulocyte specific genes. Recent data demonstrated that ICSBP also regulate the development of dentritic cells (DC) important for innate immunity. These results indicate that ICSBP plays a critical role in the differentiation of myeloid progenitor cells to antigen presenting cells, thereby negatively affecting CML pathogenesis. In addition to studying ICSBP, we have been interested in proteins that modulate chromatin. Screening a library for a conserved bromodomain motif believed to be involved in interacting with chromatin, we have isolated a novel protein of 200 kD named Brd4. Brd4 carries two bromodomains and belongs to the BET subgroup of bromodomain proteins. Although BET group proteins share a conserved domain composition, their function is unknown. We observed that Brd4 interacts with a conserved replication factor C and when Brd4 is ectopically expressed in NIH-3T3 cells cell cycle progression from G1to S is blocked indicating that Brd4 plays a critical role in the initiation of DNA replication.