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Blood, Vol. 94 No. 11 (December 1), 1999:
pp. 3772-3780
A Nuclear Factor Y (NFY) Site Positively Regulates the
Human CD34 Stem Cell Gene
Hanna S. Radomska,
Anne B. Satterthwaite,
Natalie Taranenko,
Sailaja Narravula,
Diane S. Krause, and
Daniel G. Tenen
From the Department of Medicine, Harvard Institutes of Medicine,
Harvard Medical School, Boston, MA; the Department of Laboratory
Medicine, Yale University School of Medicine, New Haven, CT; and the
Department of Microbiology, Immunology, and Molecular Genetics,
University of California, Los Angeles, CA.
Proper regulation of the human CD34 gene requires a
combinatorial action of multiple proximal and long-range, cis
elements. This report shows that, like the murine CD34 5'
untranslated region (UTR), the corresponding region of the human CD34
gene is necessary for optimal promoter activity. We localized the most
critical element of this region to base pairs +48/+75. Through
oligonucleotide competition and antibody supershift experiments in
electrophoretic mobility shift assays, we found that this sequence
contains a binding site (CCAAT box) for the transcription factor NFY
(nuclear factor Y), a factor mediating cell type-specific and
cell-cycle regulated expression of genes. Mutating this site led to a
5-fold decrease in CD34 promoter activity in transient transfection
experiments. Interestingly, NFY binds adjacently to the earlier
identified c-myb binding site. Here we show that both binding sites are
important for CD34 promoter function: mutating either site alone
decreased CD34 promoter-driven reporter gene activity 4-fold. We also
show that the integrity of the c-myb binding site is necessary for stabilization of NFY binding to its site. Such cooperation between c-myb, which is expressed in early hematopoietic cells, and NFY, which
is expressed in many cell types, might contribute to specific activation of CD34 in stem cells. The CCAAT box motif was also noted in the 5' UTR of the murine CD34 gene, however, NFY did not
bind to this region. Thus, our results indicate that the functional similarities between the human and murine CD34 5' UTRs are
achieved through different molecular mechanism(s).
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