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J. Biol. Chem., Vol. 269, Issue 31, 19757-19765, Aug, 1994
DP Wade, GE Lindahl and RM Lawn
Elevated levels of lipoprotein(a) (Lp(a)) in the plasma are a risk factor
for coronary artery disease and stroke. Plasma Lp(a) concentrations are
highly heritable and predominantly determined by the liver-specific
apolipoprotein(a) (apo(a)) gene. In this report we show by deletion
analysis that sequences from -98 to +130 of the apo(a) gene are sufficient
to direct liver-specific transcription. DNase I protection analysis of this
region using HepG2 nuclear extracts revealed six major protein-binding
sites, designated A to F. A mutation within footprint C, situated in the
5'-untranslated region of the gene, resulted in a marked reduction of
luciferase expression from a reporter construct to 12% of wild type. This
was not due to a decrease in mRNA stability. Gel mobility shift assays
demonstrated that site C binds hepatocyte nuclear factor 1 alpha (HNF-1
alpha), and overexpression of HNF-1 alpha in HepG2 cells resulted in a
significant stimulation of transcription from this promoter fragment.
Mutation of footprint B resulted in a 2-fold enhancement of transcription.
These results show that positive regulation of transcription of the apo(a)
gene is dependent on the binding of HNF-1 alpha to a regulatory element
situated downstream of the mRNA start site, and suggest that an as yet
unidentified protein may negatively regulate apo(a) transcription by
binding to a discrete sequence within the 5'-untranslated region.
Apolipoprotein(a) gene transcription is regulated by liver-enriched trans-acting factor hepatocyte nuclear factor 1 alpha
Falk Cardiovascular Research Center, Stanford University Medical School, California 94305.
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