Erythropoietin (EPO) is a very important agent for the treatment of anemias resulting from compromised EPO production. EPO plays essential roles in stimulating the growth and differentiation of erythroid progenitors during erythropoiesis. Although EPO is important for the treatment of human diseases, a little is known about the mechanisms of this agent. For instance, how it regulates growth and differentiation is poorly understood. It is the goal of this proposal to understand how EPO binding to its receptor leads to be the induction of genes such as oncogenes associated with growth and differentiation. EPO has been shown to alter protein phosphorylation on serine through activation of PK-C. Preliminary results from our laboratory demonstrate that EPO also modulates phosphorylation on tyrosines. In addition, we have demonstrated that EPA activates the activity of JUN/AP-1 enhancer element placed in front of CAT gene. Activation of both PK-C and AP-1 sequence by PMA and growth factors are associated with regulation of differentiation. In this proposal, we will examine (1) whether EPO activates FOS and JUN RNA and protein synthesis; (2) whether EPO activates c-jun transcription through the AP-1 sequence; (3) whether overexpression of c-jun is enough to induce differentiation of K562 and Rauscher cells; (4) determine whether EPO stimulates the transcription of Jun B and Jun D genes; (5) identify signal transduction molecules involved in mediating EPO's signal to the nucleus; and, (6) determine the role of AP-1 activation in regulation of globin gene synthesis by EPO. The knowledge to be obtained from this project will enable us to use EPO more effectively in the treatment of diseases and to block its activity when it functions to promote growth of neoplastic cells.
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