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Department of Pharmacology and Center for Pharmacogenetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
The human acute phase serum amyloid A (A-SAA) genes,
SAA1 and SAA2, have a high degree of
sequence identity that extends 
450 bp upstream of their
transcription start sites. Each promoter contains analogously
positioned functional binding sites for the transcription factors
NF-
B and NF-IL6. In human HepG2 hepatoma cells transfected with SAA
promoter luciferase reporter constructs, administration of IL-1 and
IL-6, singly or in combination, induced SAA1 and
SAA2 transcriptional readouts that were qualitatively
indistinguishable. However, under induced conditions, the
SAA2 promoter had a significant quantitative
transcriptional advantage over the SAA1 promoter. The
application of the synthetic glucocorticoid dexamethasone in the
context of cytokine stimulation enhanced the transcriptional activity
of the SAA1, but not the SAA2, promoter
such that readout from the former became equivalent to that from the
latter. A putative glucocorticoid response element (GRE) is present
(between residues -208 and -194) only in the SAA1
gene; a similar sequence in the corresponding region of the
SAA2 gene is disrupted by a nine-residue insertion. The
SAA1 GRE was shown to be functionally active and the
SAA2 disrupted GRE was shown to be functionally inactive
in experiments using reporter constructs carrying SAA1
and SAA2 promoters that had been modified by
site-specific mutagenesis. Quantitative analysis of transcript-specific
RT-PCR products, derived from SAA1 and SAA2 mRNAs after treatment of
HepG2 cells with cytokines in the presence or absence of dexamethasone,
confirmed that the endogenous SAA1 gene has a
cytokine-driven transcriptional disadvantage that is superseded by a
marginal transcriptional advantage when glucocorticoids are
present.
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