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). Besides having defects in macrophage functions, ICSBP-/- mice display a syndrome similar to chronic myelogenous leukemia (CML) with abnormal expansion of granulocytes. 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-/- myeloid progenitor cells by means of MSCV retrovirus vector. The ICSBP-/- progenitor cells were capable of differentiating into granulocytes in response to granulocyte colony stimulating factor (G-CSF), but did not respond to macrophage-CSF. However, upon ICSBP transduction, the myeloid progenitor cells differentiated into mature macrophages even in the absence of M-CSF. ICSBP transduced cells ceased to divide and expressed a number of macrophage specific genes, and repressed granulocyte specific genes. Mutations in ICSBP which abolished DNA binding or interaction with PU.1, a transcription factor of the Ets family completely abolished the ability to stimulate macrophage differentiation. These results indicate that ICSBP plays a critical role in the differentiation of myeloid progenitor cells to macrophages, thereby negatively affecting CML pathogenesis. Besides 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 MCAP. MCAP carries two bromodomains and belongs to the BET subgroup of bromodomain proteins, which includes yeast BDF1, Drosophila fsh and human RING3. Although BET group proteins share a conserved domain composition, their functions are almost totally unknown. We were able to show that MCAP associates with condensed chromosomes during mitosis and plays a role in the cell cycle transition from G2 to M. Our results provide the first line of evidence that MCAP and other BET proteins have an important function in cell division.