The overall objective of this proposal is to gain an understanding of signal transduction events that result in monocytic differentiation of human myeloid leukemia cells. Previous studies from this laboratory have indicated that activation of protein kinase C is associated with the appearance of a monocytic phenotype and expression of the c-fms proto- oncogene. The c-fms gene product, a transmembrane protein with tyrosine kinase activity, is identical to the CSF-1 receptor. Since CSF-1 is required for the proliferation and differentiation of monocytes, regulation of the c-fms gene is a crucial event for maturation along this lineage. The proposed studies will focus on the signaling mechanisms responsible for controlling the expression of this gene. Certain insights are now available regarding the regulation of c-fms expression. While studies with phorbol esters, bryostatin 1, and phospholipase C have implicated the activation of protein kinase C, other events may be involved in controlling the level of c-fms transcripts. In this regard, recent work has indicated that the production of arachidonic acid metabolites associated with protein kinase C activation is responsible for signals that regulate c-fms expression. Moreover, recent studies have demonstrated that the level of c-fms transcripts is controlled postranscriptionally by a labile protein. These findings have provided the experimental basis for the proposed studies. The proposed work will monitor the role of protein kinase C in the induction of c-fms during monocytic differentiation (Specific Aim 1) by employing agents known to activate and inhibit this enzyme. Furthermore, agents which are known to induce c-fms mRNA (such as 1, 25 dihydroxyvitamin D3) will metabolism in the regulation of c-fms expression will be monitored (Specific Aim 2) with the use of agents which affect this pathway at various steps. Transcriptional activation and posttranscriptional regulation of c-fms gene expression (Specific Aim 3) will be studied as events induced by signaling pathways identified monocytic differentiation in myeloid cell lines and studied for c-fms expression, protein kinase C activation, and arachidonic acid release (Specific Aim 4). These studies should provide insights regarding signaling events associated with c-fms expression and monocytic differentiation of myeloid leukemia cells. The results of these studies may also be applicable toward defining events which result in a block in differentiation characterized by clonogenic cells in human acute myeloid leukemia.
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