Granulocyte-macrophage colony stimulating factor (GM-CSF) is a very important agent for the treatment of neutropenia induced by chemotherapy and AIDS and for the treatment of hematopoietic diseases e.g. aplastic anemia. GM-CSF may also play a role in stimulating the growth of hematopoietic tumors e.g. juvenile chronic myelogenous leukemia. Although this agent is important for the treatment of human disease and possibly plays a causative role in the growth of some neoplasms, little is known about the biochemical mechanism of action of this agent. It is goal of this project to understand how GM-CSF binding to its receptor leads to the induction of genes associated with cell growth and differentiation. Preliminary results from our laboratory have demonstrated important facts about the GM-CSF receptor, the mechanism of signal transduction by GM-CSF, and the genes activated soon after GM-CSF binds to its receptor. We find that two mRNAs encode the alpha subunit of GM-CSF receptor. One of these has a single peptide but no transmembrane domain suggesting that it is secreted. We find that binding of GM-CSF to its receptor activities both tyrosine kinases and protein kinase C and that protein kinase C activation is important for the stimulation of gene transcription. Finally, we show that GM-CSF binding stimulates c-jun protooncogene transcription and activates other genes which contain the AP-1 enhancer sequence. In this proposal, we will (1) examine the role of the secreted receptor in the biologic activity of this hormone (2) study how tyrosine kinases and protein kinase C interact to mediate the effects of GM-CSF on transcription (3) determine whether protein phosphorylation mediated by GM-CSF activates binding of Fos/Jun proteins to the AP-1 enhancer sequences. In addition we will map the c-jun enhancer to determine which sequences are necessary for the transcriptional activation of this gene by GM-CSF. The results of these studies will illucidate how the binding of GM-CSF to its receptor functions to mediate gene transcription. By understanding the early events stimulated by GM-CSF, we would hope to better understand how this agent stimulates growth and differentiation of hematopoietic cells. This knowledge will enable us to use this agent more effectively in the treatment of disease and to block its activity when it functions to promote the growth of neoplastic cells.
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