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Analysis of DNA Binding Proteins Associated With Hemin-Induced
Transcriptional Inhibition. The Hemin Response Element Binding
Protein Is a Heterogeneous Complex That Includes the Ku Protein
S.V. Reddy,
O. Alcantara, and
D.H. Boldt
From the Division of Hematology, Department of Medicine, University
of Texas Health Science Center, San Antonio, TX.
Hemin inhibits transcription of the tartrate resistant acid
phosphatase (TRAP) gene. Using deletion mutagenesis of the mouse TRAP
5 -flanking region, we previously identified a 27-bp DNA segment
containing a central GAGGC tandem repeat sequence (the hemin response
element [HRE]), which bound nuclear proteins (hemin response element
binding proteins [HREBPs]) from hemin-treated cells and appeared to
be responsible for mediating transcriptional inhibition in response to
hemin. We now have used affinity binding to
HRE-derivatized beads to identify four HREBP components with apparent
molecular masses of 133-, 90-, 80-, and 37-kD,
respectively. The 80- and 90-kD components correspond to the p70 and
p80/86 subunits of Ku antigen (KuAg) as documented by partial amino
acid microsequencing of tryptic digests and immunologic reactivity. Based on reactivity of the HREBP gel shift band with antibodies to the
redox factor protein (ref1) in shift Western experiments, it is shown
that the 37-kD component represents ref1. The 133-kD component appeared
to be a unique protein. KuAg participation in HREBP complexes was
specific as it was present in HREBPs bound to HRE microcircles. Results
of depletion/reconstitution experiments suggested that KuAg does not
bind alone or directly to HRE DNA, but does so only in conjunction with
the 133- and/or 37-kD proteins. We conclude that HREBP is a
heterogeneous complex composed of KuAg, ref1, and a unique 133-kD
protein. We speculate that the role of heme may be to promote
interactions among these components, thereby facilitating HRE binding
and downregulation of hemin responsive genes.
Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1793-1801
© 1998 by The American Society of Hematology.
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