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CCAAT/Enhancer Binding Protein ε (C/EBPε) is a critical Component of Lympho-Hematopoiesis: Ryuya YAMANAKA¹, Ryuichi TANAKA¹, Michael BLAESE², and Kleanthis G. XANTHOPOULOS² (¹ Dept. of Neurosurg., Brain Res. Inst., Niigata Univ., ² Clinical Gene Therapy Branch, NHGRI, NIH)

CCAAT/Enhancer Binding Protein ε (C/EBPε) is a recently cloned member of the C/EBP family of transcription factors and is expressed exclusively in cells of lympho-hematopoietic origin. The human C/EBPε gene is transcribed by two alternative promoters, Pα and Pβ. A combination of differential splicing and alternative use of promoters generates four mRNA isoforms, of 2.6 kb and 1.3-1.5 kb in size. These transcripts can encode three proteins of calculated MW 32.2 kDa, 27.8 kDa and 14.3 kDa. C/EBPεmRNA was greatly induced during in vitro granulocytic differentiation of human primary CD34+ cells. Transient transfection experiments with expression vectors for two of the isoforms, demonstrated that the 32.2 kDa protein is an activator of transcription of G-CSF receptor promoter,　while the 14.3 kDa protein is not. Thus, C/EBPεis regulated in a complex fashion. Mice with a null mutation in C/EBPεdevelop normally and are fertile but fail to generate mature neutrophils and eosinophils. Opportunistic infections and tissue destruction lead to death by 3 to 5 months of age. Furthermore, several cytokine genes were indeed found to be affected by the absence of C/EBPε. The mRNAs encoding IFN-γ, IL-2, IL-4, IL-12p40 and to a lesser extend TNF-αwere expressed at lower levels in C/EBPε-deficient mice. Thus, C/EBPεis essential for terminal differentiation and functional maturation of committed granulocyte progenitor cells.