Defect in the regulation of 4E-BP1 and 2, two repressors of translation initiation, in the retinoid acid resistant cell lines, NB4-R1 and NE4-R2

We recently reported evidence for differential regulation of the translatio n machinery during human myeloid differentiation, specific to the monocytic /macrophage pathway or to the granulocytic pathway. A decrease in translati on rates and concomitant regulation of two repressors of translation initia tion, 4E-BP1 and 4E-BP2 (eIF4E-binding proteins 1 and 2), occur in cells in duced to differentiate along the monocytic/macrophage pathway or along the granulocytic pathway. Induction of HL-60 and U-937 cell differentiation int o monocytes/macrophages results in a dephosphorylation and consequent activ ation of 4E-BP1. In contrast, following treatment of HL-60 cells with retin oic acid (RA) which results in a granulocytic differentiation of these cell s, 4E-BP1 protein expression is decreased whereas 4E-BP2 protein expression is strongly increased. In this study, we further investigated the regulati on of 4E-BP1 and 4E-BP2 in the HA-induced differentiation process using the NB4 promyelocytic cell line and the RA maturation-resistant NB4 subclones, NB4-R1 and NB4-R2. RA treatment resulted in a decrease in 4E-BP1 protein a nd mRNA expression and concomitant increase in 4E-BP2 protein expression, i n NB4 cells, but not in NB4-RI and NB4-R2 cells. The increase in 4E-BP2 pro tein expression was not correlated to an increase in 4E-BP2 mRNA level sugg esting a post-transcriptional regulation of 4E-BP2 expression. In RA-primed cells, cAMP induce maturation of NB4-R1, but not NB4-R2 cells, cAMP treatm ent resulted in a down-regulation of 4E-BP1 protein and mRNA expression in HA-primed NB4-RI, but not N84-R2 cells. However, 4E-BP2 expression was not modified in both cell types following cAMP treatment. This indicates that 4 E-BP1 down-regulation is associated with granulocytic maturation, whereas p ost-transcriptional regulation of 4E-BP2 expression is associated with the early action of HA.