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J. Biol. Chem., Vol. 275, Issue 40, 31274-31282, October 6, 2000
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From the Laboratory of Retinal Cell and Molecular Biology, NEI,
National Institutes of Health, Bethesda, Maryland 20892
RPE65 is essential for all-trans- to
11-cis-retinoid isomerization, the hallmark reaction of the
retinal pigment epithelium (RPE). Here, we identify regulatory elements
in the Rpe65 gene and demonstrate their functional
relevance to Rpe65 gene expression. We show that the 5'
flanking region of the mouse Rpe65 gene, like the human
gene, lacks a canonical TATA box and consensus GC and CAAT boxes. The
mouse and human genes do share several cis-acting elements, including
an octamer, a nuclear factor one (NFI) site, and two E-box
sites, suggesting a conserved mode of regulation. A mouse
Rpe65 promoter/ The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF271297.
The Upstream Region of the Rpe65 Gene Confers Retinal
Pigment Epithelium-specific Expression in Vivo and in
Vitro and Contains Critical Octamer and E-box Binding Sites*
,
-galactosidase transgene containing bases -655 to +52 (TR4) of the mouse 5' flanking region was sufficient to direct high RPE-specific expression in transgenic mice, whereas shorter fragments (-297 to +52 or -188 to +52) generated only background activity. Furthermore, transient transfection of analogous TR4/luciferase constructs also directed high reporter activity in the
human RPE cell line D407 but weak activity in the non-RPE cell lines
HeLa, HepG2, and HS27. Functional binding of potential transcription
factors to the octamer sequence, AP-4, and NFI sites was demonstrated
by directed mutagenesis, electrophoretic mobility shift assay, and
cross-linking. Mutations of these sites abolished binding and
corresponding transcriptional activity and indicated that octamer and
E-box transcription factors synergistically regulate the RPE65 promoter
function. Thus, we have identified the regulatory region in the
Rpe65 gene that accounts for tissue-specific expression in
the RPE and found that octamer and E-box transcription factors play a
critical role in the transcriptional regulation of the Rpe65 gene.
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: NEI-LRCMB, National
Institutes of Health, Bldg. 6, Rm. 339, 6 Center Dr. MSC 2740, Bethesda, MD 20892-2740. Tel.: 301-496-0439; Fax: 301-402-1883; E-mail: soto@helix.nih.gov.
§
Sponsored by the Howard Hughes Medical Institute/Montgomery County
(Maryland) Public Schools/National Institutes of Health Internship Program.
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