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Volume 271, Number 31, Issue of August 2, 1996 pp. 18554-18560
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Analysis of the Megakaryocyte Glycoprotein IX Promoter Identifies Positive and Negative Regulatory Domains and Functional GATA and Ets Sites

(Received for publication, February 14, 1996, and in revised form, May 15, 1996)

From the Hematology Section, Medical and Research Services, Seattle Veterans' Affairs Medical Center, Seattle, Washington 98108 and the Division of Hematology, Department of Medicine, University of Washington, Seattle, Washington 98195

The glycoprotein (GP) Ib-V-IX multisubunit complex binds to von Willebrand factor and mediates the adhesion of platelets to the subendothelium of damaged blood vessels. Expression of the GPIX subunit is required for stability of the complex, and its absence in platelets is associated with the rare bleeding disorder Bernard-Soulier syndrome. Comparative analyses indicate that the four GPIb-V-IX subunits are members of the leucine-rich repeat family and suggest that GPIX resembles a possible primitive progenitor of this group. To characterize GPIX transcriptional regulation, a series of 5 deletion constructs was made linking the GPIX upstream flanking sequence to the luciferase marker gene, and promoter activity was measured in transiently transfected human erythroleukemia cells. This analysis identified two negative regulatory domains between 686 to 423 and 311 to 203 and two positive regulatory domains at 323 to 311 and 151 to 100 relative to the GPIX transcription start site. In addition, site-directed mutagenesis experiments and in vitro gel retardation assays identified Ets and GATA elements at 42 and 65, which positively regulate GPIX promoter activity and specifically bind nuclear factors derived from human erythroleukemia cells. DNase I protection experiments identified a protein-dependent ``footprint'' and hypersensitive site within the GPIX Ets sequence. These results provide a framework for comparison of the GPIX promoter with others of the GPIb-V-IX system, other megakaryocyte-specific genes, and other members of the leucine-rich repeat family.

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