GROWTH REGULATION IN NORMAL AND TRANSFORMED PHAGOCYTES

单核吞噬细胞的增殖和分化

The proliferation and differentiation of mononuclear phagocytes are regulated by a group of hemopoietic growth factors known as colony- stimulating factors (CSFs). In mouse, most macrophage precursor cells display several types of CSF receptors simultaneously and respond to CSFs either alone or in combination. Despite their seeming redundancy and overlap in biologic effects, CSFs act in a hierarchical and coordinated manner toward the control of macrophage proliferation and differentiation. Receptor binding assay indicates that although CSFs do not share each other's receptor sites, they can induce a rapid transient down-regulation of other CSF receptors. However, although J774 monocyte-like tumor cells display multiple CSF receptor systems, they do not exhibit the receptor trans-modulation seen in their normal counterparts. Our working hypothesis is that various CSF receptors are linked through a signaling network by which the processes of proliferation and differentiation in hemopoietic cells are coupled. It is thought that the un-coupling between CSF receptors in hemopoietic cells may lead to the arrested differentiation and uncontrolled proliferation characteristic of leukemic cells. To verify that hypothesis, we will first study the biochemical changes associated with receptor trans-modulation and their biologic significance in normal macrophages and their leukemic counterparts, J774 cells. Next, we will study the biochemical basis responsible for receptor-receptor interaction and determine the causes leading to receptor-uncoupling seen in leukemic cells. Finally, we will study whether the biologic responses associated with receptor trans-modulation are regulated at genetic levels as well. The overall objective of this proposal is to gain more insight into the biologic significance of receptor-receptor interaction and the role of this interaction in linking the processes of proliferation and differentiation in hemopoietic cells.