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Subunit
(Received for publication, January 6, 1997, and in revised form, February 24, 1997)
From the Erythropoietin Group, Institute of Molecular Medicine,
John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
Hypoxia-inducible factor-1 (HIF-1), a
heterodimeric DNA binding complex composed of two
basic-helix-loop-helix Per-AHR-ARNT-Sim proteins (HIF-1
and -1
),
is a key component of a widely operative transcriptional response
activated by hypoxia, cobaltous ions, and iron chelation. To identify
regions of HIF-1 subunits responsible for oxygen-regulated activity, we
constructed chimeric genes in which portions of coding sequence from
HIF-1 genes were either linked to a heterologous DNA binding domain or
encoded between such a DNA binding domain and a constitutive activation
domain. Sequences from HIF-1 but not HIF-1 conferred
oxygen-regulated activity. Two minimal domains within HIF-1 (amino
acids 549-582 and amino acids 775-826) were defined by deletional
analysis, each of which could act independently to convey inducible
responses. Both these regions confer transcriptional activation, and in
both cases adjacent sequences appeared functionally repressive in
transactivation assays. The inducible operation of the first domain,
but not the second, involved major changes in the level of the
activator fusion protein in transfected cells, inclusion of this
sequence being associated with a marked reduction of expressed protein
level in normoxic cells, which was relieved by stimulation with
hypoxia, cobaltous ions, or iron chelation. These results lead us to
propose a dual mechanism of activation in which the operation of an
inducible activation domain is amplified by regulation of transcription factor abundance, most likely occurring through changes in protein stability.
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