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Blood, Vol. 94 No. 10 (November 15), 1999:
pp. 3366-3380
Functional Characterization of the Human Platelet Glycoprotein V Gene
Promoter: A Specific Marker of Late Megakaryocytic Differentiation
Adeline Lepage,
Georges Uzan,
Nadège Touche,
Martine Morales,
Jean-Pierre Cazenave,
François Lanza, and
Corinne de
la Salle
From INSERM U. 311, Etablissement de Transfusion Sanguine de
Strasbourg, Strasbourg, France; and INSERM U. 506, Hôpital Paul
Brousse, Villejuif, France.
Glycoprotein V (GPV), a subunit of the platelet GPIb-V-IX receptor
for von Willebrand factor and thrombin, is specifically found in
platelets and mature megakaryocytes. Studies of the GPV gene can
therefore provide insight into the mechanisms governing megakaryocyte
differentiation. The human GPV promoter was isolated, and elements
important for its tissue specific transcriptional activity were
localized using systematic DNase I protection and reporter deletion
assays. A  1413/+25 fragment inserted into a luciferase reporter
construct displayed promoter activity in Dami and HEL but not in K562,
HL60, or HeLa cells. Progressive 5' to 3' deletion showed a
putative enhancer region in the 1413/903 segment that contained
closely spaced GATA and Ets sites protected from DNase I digestion in
Dami extracts. Regions similar to a GPIIb gene repressor were found at
816 and 610, with the first exhibiting repressor activity in Dami
and HEL cells and the second protected from DNAse I. Deletions from
362 to 103, an area containing protected sites for Sp1, STAT, and
GATA, induced a progressive decrease in activity. The 103/+1
fragment, bearing a proximal Ets footprinted site and a GATA/Ets tandem
footprint, displayed 75% activity relative to the full-length promoter
and retained cell specificity. In summary, this work defines several
regions of the GPV gene promoter important for its activity. It
contains megakaryocyte-specific signals, including
erythro-megakaryocytic GATA, and Ets cis-acting elements, GPIIb-like
repressor domains, and binding sites for ubiquitous factors such as
Sp1, ETF, and STAT.
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