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Blood, 15 November 2002, Vol. 100, No. 10, pp. 3578-3587
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Furin gene (fur) regulation in differentiating human
megakaryoblastic Dami cells: involvement of the proximal GATA
recognition motif in the P1 promoter and impact on the maturation
of furin substrates
Marie-Hélène Laprise,
Francine Grondin,
Pauline Cayer,
Patrick P. McDonald, and
Claire M. Dubois
From the Immunology Division, Department of Pediatrics,
Faculty of Medicine, University of Sherbrooke, Québec, PQ,
Canada.
The convertase furin is involved in the maturation of key
growth/aggregation mediators synthesized by the platelet producers, megakaryocytes, but the regulation of furin in these cells remains unknown. Computer-assisted search of the furin promoter sequence revealed multiple potential binding motifs for GATA-1, suggesting that
furin is expressed and regulated in these cells. Using megakaryoblastic Dami cells, we observed that fur mRNA expression increased
gradually on phorbol 12-myristate 13-acetate-induced differentiation,
reaching maximum levels (8.3-fold increase) at 10 days. Transient
transfections with P1, P1A, or P1B fur-LUC-promoter
constructs revealed that in Dami cells, the P1 promoter is the
strongest and the most sensitive to forced expression of GATA-1.
Coexpression of GATA-1 and its comodulator, Friend of GATA-1 (FOG-1),
resulted in a cooperative increase in P1 activity. Deletion analysis
indicated that important GATA-1-regulated sequences are located in the
most proximal region of the P1 promoter. Further analysis revealed 2 potential GATA-binding motifs at positions  66 and +62. Point mutation
of each of the 2 motifs indicated that the intactness of the first GATA
site is required for full basal and GATA-1-stimulated promoter
activity. Finally, the inhibition of furin activity through gene
transfer of the inhibitor  1-AT-PDX led to a block in maturation of
the furin substrates transforming growth factor- 1 and
platelet-derived growth factor. Taken together, these results indicate
that the most proximal GATA element in the P1 promoter is needed for
fur gene expression in megakaryoblastic cells. They also
suggest that proper regulation of the fur gene in
megakaryocytes has an impact on the activation of furin substrates
involved in megakaryocyte maturation and platelet functions.
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