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Blood, 1 January 2003, Vol. 101, No. 1, pp. 311-317
PHAGOCYTES
GA-binding protein (GABP) and Sp1 are required, along with
retinoid receptors, to mediate retinoic acid responsiveness of CD18
( 2 leukocyte integrin): a novel mechanism of
transcriptional regulation in myeloid cells
Thomas S. Bush,
Michele St. Coeur,
Karen K. Resendes, and
Alan G. Rosmarin
From the Department of Molecular Biology, Cell Biology
and Biochemistry, Brown University; the Division of Hematology, Brown
University Department of Medicine; and the Division of
Hematology/Oncology, The Miriam Hospital, Providence, RI.
CD18 ( 2 leukocyte integrin) is transcriptionally
regulated in myeloid cells, but the mechanisms that increase its
expression in response to retinoic acid (RA) have not been defined. The
CD18 promoter was activated by RA treatment in stably transfected U937 myeloid cells. We identified a retinoic acid response element (RARE)
that lies nearly 900 nucleotides upstream of the CD18 transcriptional start site that was bound by the RA receptors, retinoic acid
receptor (RAR) and retinoic X receptor (RXR). This RARE
accounted for one half of the RA responsiveness of CD18. However,
unexpectedly, one half of the dynamic response to RA was mediated by
the 96-nucleotide CD18 minimal promoter, which lacks a recognizable
RARE. Binding sites for the ets transcription factor,
GA-binding protein (GABP), and Sp1 were required for full RA
responsiveness of both the CD18 minimal promoter and the full-length
promoter. The ets sites conferred RA responsiveness on an
otherwise unresponsive heterologous promoter, and RA responsiveness was
directly related to the number of ets sites. The
transcriptional coactivator p300/CBP physically interacted with GABP in
vivo, and p300 increased the responsiveness of the CD18 promoter to RA.
These studies demonstrate a novel role for non-RAR transcription
factors in mediating RA activation in myeloid cells. They support the
concept that transcription factors other than RARs are required for
RA-activated gene expression. We hypothesize that a multiprotein
complex an enhanceosomethat includes GABP, other transcription
factors, and coactivators, dynamically regulates CD18 expression in
myeloid cells.
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