Cyclic AMP Responsive Element Binding Proteins Are Involved in 'Emergency' Granulopoiesis through the Upregulation of CCAAT/Enhancer Binding Protein β.

Hirai, Hideyo, Kamio, Naoka, Huang, Gang, Matsusue, Akiko, Ogino, Shinpei, Kimura, Nobuhiko, Satake, Sakiko, Ashihara, Eishi, Imanishi, Jiro, Tenen, Daniel G, Maekawa, Taira

In contrast to the definitive role of the transcription factor, CCAAT/Enhancer binding protein α (C/EBPα), in steady-state granulopoiesis, previous findings have suggested that granulopoiesis during emergency situations, such as infection, is dependent on C/EBPβ. In this study, a novel lentivirus-based reporter system was developed to elucidate the molecular switch required for C/EBPβ-dependency. The results demonstrated that two cyclic AMP responsive elements (CREs) in the proximal promoter region of C/EBPβ were involved in the positive regulation of C/EBPβ transcription during granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced differentiation of bone marrow cells. In addition, the transcripts of CRE binding (CREB) family proteins were readily detected in hematopoietic stem/progenitor cells. CREB was upregulated, phosphorylated and bound to the CREs in response to GM-CSF stimulation. Retroviral transduction of a dominant negative CREB mutant reduced C/EBPβ mRNA levels and significantly impaired the proliferation/differentiation of granulocyte precursors, while a constitutively active form of CREB facilitated C/EBPβ transcription. These data suggest that CREB proteins are involved in the regulation of granulopoiesis via C/EBPβ upregulation.

Cyclic AMP Responsive Element Binding Proteins Are Involved in 'Emergency' Granulopoiesis through the Upregulation of CCAAT/Enhancer Binding Protein β.

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