Molecular mechanisms of regulation of proliferation, differentiation and death of hematopietic cells by CREB/ATF family proteins : an application to molecular-targeted therapy of hematopoietic malignancies

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We evaluated the involvement of cAMP-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 CRE-dependent transcription activity and induced a wide variety of differentiation phenotypes including the functional and morphological maturation. Indeed, ATRA treatment induced an expression of CCAAT/enhancer-binding protein β (C/EBPβ), a CRE-dependent transcription factor important for monocytic differentiation, and the inhibition of CRE enhancer activity by the expression of a dominant negative cAMP-response element-binding protein (dominant negative CREB, dn-CREB) abolished the induction of C/EBPβ. Functional maturation such as an enhancement in cell adhesion and respiratory burst activity were dramatically suppressed by the expression of dn-CREB. In accordance with these, the differentiation-dependent induction of adhesion molecule (CD11b), the phagocyte oxidase for the respiratory burst and the transcription factor PU.1 responsible for the phagocyte oxidase induction was all eradicated by dn-CREB. Quite surprisingly, morphological maturation including nuclear convolution and cytoplasmic vacuolar formation were augmented by dn-CREB. Under the same condition, 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 the single process of myeloid differentiation : it stimulates functional maturation but suppresses morphological maturation while giving no effects on cell growth arrest.