The macrophage-colony stimulating factor receptor (Fms) regulates monocyte/macrophage growth, development, survival, and mature cell functions. It is also involved in placenta development and perhaps embryo implantation through expression in trophoblast cells and in the decidual cells surrounding the developing egg cylinder. Abnormal Fms expression has been detected in breast, ovarian, and B cell tumors, where it may play some role in tumor progression and metastasis. In addition, oncogenic versions of Fms have been isolated and mutations resulting in activation defined. In normal cells, Fms transmits highly coordinated signals for growth and differentiation, whereas in tumor cells these signals are destroyed or unregulated. The major aim of this proposed project is to define the molecular signals for the growth and differentiation pathways and examine the mechanisms for coordinate regulation of these two Fms- controlled events. The pathway for growth probably follows the defined sequence described in other systems (i.e., activation of Ras leading to MAP kinase activation and then transcription factor activation); however, the pathway for differentiation signaling is undefined and these studies will concentrate on this pathway. Using mutations of Fms that do, or do not signal differentiation, pathways will be defined by biochemical and genetic techniques utilizing immunoprecipitation and the yeast two-hybrid system. Functional studies will be performed by cloning cDNAs for the proteins of the pathway and expressing activated or dominant-negative forms of these proteins in FDC-P1 cells using cell differentiation as the readout signal. In addition, differentiation signals in the nucleus will be characterized by cloning genes specific for Fms differentiation signals. Analysis of promoter regions for these genes and their interacting transcription factors will then give additional differentiation signals that will be used to measure differentiation signaling, and traced back to the Fms signals originating from the plasma membrane. Finally, the coordinate regulation of growth and differentiation will be examined by looking for common regulation points in each pathway. These studies will facilitate our understanding of why leukemias grow but fail at differentiation, and perhaps provide targets for rational intervention of growth or stimulation of differentiation.
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