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Regulated Expression of the Human Complement C4 Promoter1
Department of Biochemistry, University of Western Australia, Nedlands, Australia
The fourth component of human complement (C4) is a serum protein
that is expressed in the liver and other organs. The promoter region of
the C4 gene has been analyzed in reporter gene assays in two cell lines
that represent hepatic (HepG2) and monocytic (U937) lineages. Analysis
indicated that regions important for basal transcription in HepG2 cells
included Sp1 and E box sites within the first 100 bp upstream of the
transcription initiation site but not the nuclear factor-1 site
important in the control of the mouse C4 gene. Also, a region
encompassing -468 to -310 was able to repress activity 2-fold.
However, when a CACCC or GT box sequence at -140 was mutated the
repressive activity of the upstream region resulted in almost no
activity. The -140 region consists of a series of four closely
positioned GT boxes that were shown to bind Sp1, Sp3, and basic
Krupple-like factor in EMSA. This novel two-part regulatory element may
be involved in the regulated expression of C4. However, IFN-
a major
activator of C4 expression did not signal through this two-part
regulatory element. We were able to map the position of an IFN-
responsive element in U937. IFN- was able to increase transcription
by up to 20-fold with mutations in the E box sequence at -78 to -73,
thus completely abolishing induction. We conclude that the E box
binding factors, which appear to be distinct from upstream stimulatory
factors 1 and 2, are totally responsible for IFN- induction of
C4.
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