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J Biol Chem, Vol. 273, Issue 32, 20066-20072, August 7, 1998
From the Departments of Rieger syndrome is an autosomal-dominant
developmental disorder that includes glaucoma and mild craniofacial
dysmorphism in humans. Mutations in the Pitx2 homeobox gene
have been linked to Rieger syndrome. We have characterized wild type
and mutant Pitx2 activities using electrophoretic mobility shift
assays, protein binding, and transient transfection assays. Pitx2
preferentially binds the bicoid homeodomain binding site
and transactivates reporter genes containing this site. The combination
of Pitx2 and another homeodomain protein, Pit-1, yielded a synergistic
55-fold activation of the prolactin promoter in transfection assays.
Addition of Pit-1 increased Pitx2 binding to the bicoid
element in electrophoretic mobility shift assays. Furthermore, we
demonstrate specific binding of Pit-1 to Pitx2 in vitro.
Thus, wild type Pitx2 DNA binding activity is modulated by
protein-protein interactions. We next studied two Rieger mutants. A
threonine to proline mutation (T68P) in the second helix of the
homeodomain retained DNA binding activity with the same apparent
KD and only about a 2-fold reduction in the
Bmax. However, this mutant did not
transactivate reporter genes containing the bicoid site.
The mutant Pitx2 protein binds Pit-1, but there was no detectable
synergism on the prolactin promoter. A second mutation (L54Q) in a
highly conserved residue in helix 1 of the homeodomain yielded an
unstable protein. Our results provide insights into the potential
mechanisms underlying the developmental defects in Rieger syndrome.
The Molecular Basis of Rieger Syndrome
ANALYSIS OF PITX2 HOMEODOMAIN PROTEIN ACTIVITIES
,,
Physiology and Biophysics and
¶ Pediatrics, University of Iowa, Iowa City, Iowa
52242
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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