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Blood, 15 March 2001, Vol. 97, No. 6, pp. 1721-1726
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Allele-dependent transcriptional regulation of the
human integrin  2 gene
Beatrice Jacquelin,
Michael
D. Tarantino,
Marcie Kritzik,
Diana Rozenshteyn,
James A. Koziol,
Alan T. Nurden, and
Thomas J. Kunicki
From the Roon Research Center for Arteriosclerosis and
Thrombosis, Division of Experimental Hemostasis and Thrombosis of the
Department of Molecular and Experimental Medicine, and the Department
of Vascular Biology, The Scripps Research Institute, La Jolla, CA.
Genetically controlled variation in
 2 1 expression by human blood platelets
was previously described. Sixty-two haplotype sequences corresponding
to the proximal 5' regulatory region ( 1096 to +1) of the
2 gene were compared, and a dimorphic sequence 52C>T
was identified that is located precisely between 2 tandem Sp1/Sp3
binding elements previously shown to be absolutely required for
transcriptional activity of this gene in epithelial cell lines and the
erythroleukemic cell line K562. The gene frequency of 52T in a random
Caucasian population is approximately 0.35, and the expression of 52T
correlates directly with reduced densities of platelet
21. In mobility shift analyses, the 52T
substitution attenuates complex formation with both Sp1 and Sp3. When
transfected into the erythroleukemia cell line Dami,
promoter-luciferase constructs bearing the 52T sequence exhibit a
5-fold decrease in activity relative to the 52C
construct. In transfected CHRF-288-11 megakaryocytic cells, the
corresponding activity decreases by 10-fold. The 52T sequence appears
to be in linkage disequilibrium with the previously defined allele A3
(807C; HPA-5b), known to be associated with diminished expression of
platelet 21. In summary, a natural dimorphism has been identified within the proximal 5' regulatory region
of the human integrin 2 gene that is responsible for
decreased expression levels of the integrin
21 on blood platelets through a mechanism
that is probably mediated by the nuclear regulatory proteins Sp1 and Sp3.
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