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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Activating Transcription Factor 2
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CCAAT-Enhancer-Binding Protein-beta / biosynthesis
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CCAAT-Enhancer-Binding Protein-beta / genetics
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CD11b Antigen / biosynthesis
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CD11b Antigen / genetics
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Cell Adhesion / physiology
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Cell Differentiation / drug effects
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Cell Nucleus / ultrastructure
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Cyclic AMP / physiology*
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Cyclic AMP Response Element-Binding Protein / biosynthesis
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Cyclic AMP Response Element-Binding Protein / genetics
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / physiology
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Genes, Dominant
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Genes, Reporter
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Humans
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Intercellular Adhesion Molecule-1 / biosynthesis
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Intercellular Adhesion Molecule-1 / genetics
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Myeloid Cells / cytology
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Myeloid Cells / drug effects*
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NADPH Oxidases
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Phenotype
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Phosphoproteins / biosynthesis
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Phosphoproteins / genetics
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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Regulatory Sequences, Nucleic Acid
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Respiratory Burst / physiology
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Second Messenger Systems / drug effects
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Second Messenger Systems / physiology*
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Trans-Activators / biosynthesis
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Trans-Activators / genetics
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Transcription Factors / biosynthesis
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Transcription Factors / genetics
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Transcription, Genetic / drug effects*
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Transformation, Genetic
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Tretinoin / pharmacology*
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U937 Cells / cytology
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U937 Cells / drug effects
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Vacuoles / ultrastructure
Substances
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Activating Transcription Factor 2
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CCAAT-Enhancer-Binding Protein-beta
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CD11b Antigen
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Cyclic AMP Response Element-Binding Protein
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Neoplasm Proteins
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Phosphoproteins
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Proto-Oncogene Proteins
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Trans-Activators
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Transcription Factors
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neutrophil cytosol factor 67K
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proto-oncogene protein Spi-1
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Intercellular Adhesion Molecule-1
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Tretinoin
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Cyclic AMP
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NADPH Oxidases
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neutrophil cytosolic factor 1