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Blood, 15 August 2000, Vol. 96, No. 4, pp. 1348-1357
HEMATOPOIESIS
Identification of a GATA-overlapping sequence within the enhancer
of the murine GPIIb promoter that induces transcriptional deregulation
in human K562 cells
Patricia Albanese,
Marylène Leboeuf,
Jean-Philippe Rosa, and
Georges Uzan
From INSERM U.506 and INSERM U.268, Hôpital Paul
Brousse, Villejuif, France, and INSERM U.348, Hôpital
Lariboisière, Paris, France.
The human and the murine glycoprotein platelet IIb (GPIIb)
promoters are megakaryocyte specific in human and murine cell systems, respectively. Here we show that the murine promoter is, however, highly
active when transfected in K562 human cells in which the human promoter
is almost inactive. A murine promoter, in which the enhancer element
was replaced by the human, retrieves its megakaryocytic specificity in
human cell lines. The human and murine GATA-binding sites located in
the enhancer region display slight sequence divergence next to the
consensus GATA core sequence. Gel shift experiments show that, although
the murine and the human GATA sequences both bind GATA-1, the murine
sequence alone forms an additional complex (B) not detected with the
human sequence. When the murine GATA-containing region is replaced by
the human in the context of the murine GPIIb promoter, megakaryocyte
specificity is restored in the human cell lines. A G nucleotide 3' to
GATA appears crucial because its substitution abrogates B but not
GATA-1 binding and restores megakaryocyte specificity to the murine
promoter. Conversely, substitution of the human GATA-1 binding sequence by its murine homologue that binds both GATA-1 and complex B induces an
abnormal activity for the human promoter in K562 cells. Altogether, our
data suggest that limited changes in the GATA-containing enhancer of
the GPIIb promoter can induce the recruitment of accessory proteins
that could be involved in alteration of a megakaryocyte-restricted gene
activation program.
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