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J Biol Chem, Vol. 274, Issue 53, 38097-38106, December 31, 1999
, and
From the Department of Pediatrics and the Metabolic Research Unit,
University of California, San Francisco,
San Francisco, California 94143-0978
The CYP21 gene, which encodes
P450c21, the adrenal steroid 21-hydroxylase needed for glucocorticoid
synthesis, lies in the major histocompatibility locus only 2.3 kilobase
pairs (kb) downstream from the C4 gene. A 300-base pair
(bp) proximal promoter and two upstream regions within C4
are needed for expression of mouse CYP21; the human gene
also has a proximal promoter, but upstream elements have not been
studied. To search for upstream regulatory elements in human
CYP21B, we examined up to 9 kb of 5'-flanking DNA by
transient transfection into human adrenal NCI-H295A cells. The 300-bp
proximal promoter had substantial activity, but constructs retaining
the DNA between 
4.6 and 5.6 kb had increased activity, indicating
the presence of distal elements. This region does not correspond to the
mouse upstream regions, lying further upstream within intron 35 of
C4B, which encompasses the previously described "Z
promoter." DNase I footprinting located two elements, F1 and F2,
lying 186 to 195 bp and 142 to 151 bp upstream from the Z cap
site (4862 to 4871 and 4818 to 4827 bp upstream of the CYP21B cap site). Each element formed a specific
DNA-protein complex and conferred orientation-independent expression to
a heterologous promoter. Mutations abolished formation of the
DNA-protein complexes but only partially decreased expression. We
identified a third site, F3, lying at 33 to 42 bp from Z. Competitive gel mobility supershift assays and co-transfection studies
with SF-1 produced in vitro indicate F2 and F3 bind SF-1;
BLAST searches and Southwestern blotting suggest that NF-W2 may bind
F1. These results indicate that the Z promoter is a component of the
CYP21 promoter needed to drive its adrenal-specific
expression and that CYP21 transcription elements within
C4 have kept these two genes linked during evolution.
Supported in part by the International Scholars program of the
Lawson Wilkins Pediatric Endocrine Society.
§
To whom all correspondence should be addressed: Dept. of
Pediatrics, Bldg. MR-IV, Rm. 209, University of California, San
Francisco, San Francisco, CA 94143-0978.
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