title: Defect in the regulation of 4E-BP1 and 2, two repressors of translation initiation, in the retinoid acid resistant cell lines, NB4-R1 and NB4-R2.
abstract: We recently reported evidence for differential regulation of the translation machinery during human myeloid differentiation, specific to the monocytic/macrophage pathway or to the granulocytic pathway. A decrease in translation rates and concomitant regulation of two repressors of translation initiation, 4E-BP1 and 4E-BP2 (eIF4E-binding proteins 1 and 2), occur in cells induced to differentiate along the monocytic/macrophage pathway or along the granulocytic pathway. Induction of HL-60 and U-937 cell differentiation into monocytes/macrophages results in a dephosphorylation and consequent activation of 4E-BP1. In contrast, following treatment of HL-60 cells with retinoic acid (RA) which results in a granulocytic differentiation of these cells, 4E-BP1 protein expression is decreased whereas 4E-BP2 protein expression is strongly increased. In this study, we further investigated the regulation of 4E-BP1 and 4E-BP2 in the RA-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 and mRNA expression and concomitant increase in 4E-BP2 protein expression, in NB4 cells, but not in NB4-R1 and NB4-R2 cells. The increase in 4E-BP2 protein expression was not correlated to an increase in 4E-BP2 mRNA level suggesting a post-transcriptional regulation of 4E-BP2 expression. In RA-primed cells, cAMP induce maturation of NB4-R1, but not NB4-R2 cells. cAMP treatment resulted in a down-regulation of 4E-BP1 protein and mRNA expression in RA-primed NB4-R1, but not NB4-R2 cells. However, 4E-BP2 expression was not modified in both cell types following cAMP treatment. This indicates that 4E-BP1 down-regulation is associated with granulocytic maturation, whereas post-transcriptional regulation of 4E-BP2 expression is associated with the early action of RA.
authors.affiliation: INSERM U.365, Institut Curie, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Grolleau
authors.forename: J
authors.initials: J
authors.lastname: Wietzerbin
authors.forename: L
authors.initials: L
authors.lastname: Beretta
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000187:drug effects; D002999:Clone Cells / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D039642:Eukaryotic Initiation Factors; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006098:Granulocytes; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000473:pathology*; D023461:Myeloid Progenitor Cells / Q000187:drug effects / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D010442:Peptide Chain Initiation, Translational; D010448:Peptide Initiation Factors / Q000096:biosynthesis* / Q000235:genetics; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000235:genetics; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D015290:Second Messenger Systems; D013873:Thionucleotides / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C104151:EIF4EBP2 protein, human; D039642:Eukaryotic Initiation Factors; D009363:Neoplasm Proteins; D010448:Peptide Initiation Factors; D010750:Phosphoproteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D012097:Repressor Proteins; D013873:Thionucleotides; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D014212:Tretinoin; D000242:Cyclic AMP