Distinct involvement of cAMP-response element-dependent transcriptions in functional and morphological maturation during retinoid-mediated human myeloid differentiation.

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.