TRANSCRIPTIONAL REGULATION OF PHOSPHOPROTEIN P18 DURING MONOCYTIC DIFFERENTIATION OF U937 LEUKEMIC-CELLS

Differentiation of leukemic cells is frequently associated with downre gulation of expression of genes that are important for cell proliferat ion and differentiation. The p18 gene encodes a major cytosolic phosph oprotein that appears to play a role in transducing signals that contr ol the proliferation and differentiation of normal and leukemic cells. Recent reports have shown that p18 expression and phosphorylation by p34(cdc2) kinase is essential for progression through the cell cycle. It was previously shown that the level of p18 gene expression is marke dly reduced when several different leukemic cell lines are induced to differentiate by exposer to a variety of chemical inducers. The mechan ism of this downregulation of p18 mRNA expression has not been elucida ted. We have explored the mechanism(s) of p18 mRNA downregulation in U 937 promonocytic leukemia cells that are induced with phorbol esters t o differentiate along a monocyte/macrophage pathway. We find that the half-life of p18 mRNA that is exceptionally stable in uninduced U937 c ells does not change significantly with induced differentiation. We al so determined that the stability of the p18 mRNA in these cells does n ot depend on the synthesis of a labile protein. Direct comparison of t he transcription of this gene in induced and uninduced U937 cells show ed that transcription is the predominant level of regulation of the ac tivity of this gene in leukemic cells.