Transcriptional regulation of phosphoprotein p18 during monocytic differentiation of U937 leukemic cells.

Differentiation of leukemic cells is frequently associated with downregulation of expression of genes that are important for cell proliferation and differentiation. The p18 gene encodes a major cytosolic phosphoprotein that appears to play a role in transducing signals that control the proliferation and differentiation of normal and leukemic cells. Recent reports have shown that p18 expression and phosporylation by p34cdc2 kinase is essential for progression through the cell cycle. It was previously shown that the level of p18 gene expression is markedly reduced when several different leukemic cell lines are induced to differentiate by exposer to a variety of chemical inducers. The mechanism of this downregulation of p18 mRNA expression has not been elucidated. We have explored the mechanism(s) of p18 mRNA downregulation in U937 promonocytic leukemia cells that are induced with phorbol esters to differentiate along a monocyte/macrophage pathway. We find that the half-life of p18 mRNA that is exceptionally stable in uninduced U937 cells does not change significantly with induced differentiation. We also determined that the stability of the p18 mRNA in these cells does not depend on the synthesis of a labile protein. Direct comparison of the transcription of this gene in induced and uninduced U937 cells showed that transcription is the predominant level of regulation of the activity of this gene in leukemic cells.