title: Distinct involvement of cAMP-response element-dependent transcriptions in functional and morphological maturation during retinoid-mediated human myeloid differentiation.
abstract: We evaluated the involvement of cyclic adenosine monophosphate-response element (CRE)-dependent transcriptions in all-trans retinoic acid (ATRA)-induced myeloid differentiation using human monoblastic U937 cells. ATRA treatment caused an increment in the CRE-dependent transcription activity and induced a wide variety of differentiation phenotypes including functional and morphological maturation. Indeed, ATRA treatment induced the expression of CCAAT/enhancer-binding protein beta (C/EBPbeta), a CRE-dependent transcription factor important in monocytic differentiation, and the inhibition of CRE-enhancer activity by the expression of a dominant-negative CRE-binding protein (dn-CREB) abolished the induction of C/EBPbeta. Functional maturation, such as the enhancement of cell adhesion and respiratory burst activity, was dramatically suppressed by the expression of dn-CREB. In addition, the differentiation-dependent induction of an adhesion molecule (CD11b), the phagocyte oxidase required for respiratory burst, and the transcription factor PU.1 responsible for phagocyte oxidase induction were all abolished by dn-CREB. Surprisingly, morphological maturation, including nuclear convolution and cytoplasmic vacuolar formation, was augmented by dn-CREB. Under the same conditions, the differentiation-associated cell-growth arrest was not affected by the expression of dn-CREB. Our results clearly indicate that CRE-driven transcription plays at least three distinct roles during myeloid differentiation: It stimulates functional maturation but suppresses morphological maturation and has no effects on cell-growth arrest.
authors.affiliation: Department of Hematology, Research Institute, International Medical Center of Japan, Tokyo.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Saeki
authors.forename: Koichi
authors.initials: K
authors.lastname: Saeki
authors.forename: Akira
authors.initials: A
authors.lastname: Yuo
mesh_terms: D051698:Activating Transcription Factor 2; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000096:biosynthesis / Q000235:genetics; D039481:CD11b Antigen / Q000096:biosynthesis / Q000235:genetics; D002448:Cell Adhesion / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000648:ultrastructure; D000242:Cyclic AMP / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D005799:Genes, Dominant; D017930:Genes, Reporter; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects*; D019255:NADPH Oxidases; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D010641:Phenotype; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid; D016897:Respiratory Burst / Q000502:physiology; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology*; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*; D014170:Transformation, Genetic; D014212:Tretinoin / Q000494:pharmacology*; D020298:U937 Cells / Q000166:cytology / Q000187:drug effects; D014617:Vacuoles / Q000648:ultrastructure; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D051698:Activating Transcription Factor 2; D022782:CCAAT-Enhancer-Binding Protein-beta; D039481:CD11b Antigen; D000242:Cyclic AMP; D017362:Cyclic AMP Response Element-Binding Protein; D018799:Intercellular Adhesion Molecule-1; D019255:NADPH Oxidases; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D014212:Tretinoin; D000099232:Proto-Oncogene Protein Spi-1; C079789:neutrophil cytosol factor 67K; C060505:neutrophil cytosolic factor 1