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Characterization of regulatory elements in the 5'-flanking region of the
rat GPIIb gene by studies in a primary rat marrow culture system
KL Block, K Ravid, QH Phung and M Poncz
Department of Pediatrics, University of Pennsylvania School of Medicine,
Philadelphia.
Glycoprotein (GP)IIb/IIIa, an integrin complex found on the surface of
platelets, is a receptor for fibrinogen and other ligands, and is involved
in platelet aggregation. Because GPIIb is specifically expressed in
megakaryocytes, we have studied the 5'-flanking region of the rat (r) GPIIb
gene as a model of a megakaryocyte-specific gene. The studies presented
here used a rat marrow expression system, which allows the study of primary
cells undergoing terminal differentiation into megakaryocytes. The
determination of megakaryocyte-specific expression of DNA constructs was
possible by immunomagnetically separating megakaryocytes from total bone
marrow cells. Transient expression constructs, containing varying lengths
of the 5'-flanking region from -39 to -912 bp, localized a regulatory
element between -460 and -439 bp upstream of the transcriptional start
site. This region contains a GATA consensus binding element between -457
and -454 (GATA454). Further constructs demonstrated that this GATA binding
element was indeed essential for expression. A 25-bp substitution, covering
the region -450 to -426 immediately downstream of the GATA454, demonstrated
that this region was essential for full expression, which suggests that
this region may interact with the GATA454 site in promoting high-level
lineage-specific expression. To define regulatory elements between the
GATA454 and the transcriptional start site further, we tested additional
constructs derived from the original -912 construct; each of which
contained the GATA454 but had different 50-bp deletions from -450 to the
start site. Virtually all of these constructs continued to show high-level
tissue-specific expression. The deleted -150 to -101 construct had twice
the level of expression of the full-length wild-type construct; therefore,
this region may contain a negative regulatory element. Comparison of our
data with expression studies performed with the 5'-region of the human
GPIIb gene using HEL cells, a cell line with some megakaryocytic
properties, demonstrates significant differences, which may reflect our use
of primary rate bone marrow cells. In particular, our study points to the
importance of the GATA454 for high levels of GPIIb expression in developing
megakaryocytes.
Volume 84,
Issue 10,
pp. 3385-3393,
11/15/1994
Copyright © 1994 by The American Society of Hematology
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