Regulation of gene expression in erythropoiesis

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The induced differentiation of murine erythroleukemia(MEL) cells in vitro is a good system to analyze the molecular events underlining the commitment process of cell differentiation. We found that TSA8 cells, one of MEL cells were committed to respond to erythropoietin(epo) and to form the differentiated colonies of erythroid progenitor cells, when the cells were treated with DMSO. In the induced process, the surface receptors for epo did not change in their number and in their affinities, thus, the intracellular factors induced in the cells are required for the acquisition of responsiveness to epo. The involvement of two independent factors are shown to be required for the commitment; one is the cycloheximide-sensitive factor which appears just after the addition of DMSO, the other is the Na^+/H^+ transporter which is sensitive to anyloride derivatives and appears in the later process of commitment. Thus, the commitment may be controlled by the sequential appearance of two factors, The signal transduction induced by epo was analyzed and the results indicated that a cAMP pathway is mainly involved in the epo action.To examine the involvement of cellular onco genes in the commitment process, the methallothionein promoter-linked c-myc gene was introduced into MEL cells and the effect of the regulated, but over-produced c-myc products was analyzed. The results indicated that the level of c-myc determines the probability of commitment of differentiation of Mel cells, Furthermore, c-myc may function to link the commitment process and the timing of expression of tissue-specific genes.