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ABCD2 is a direct target of β-catenin and TCF-4: implications for X-linked adrenoleukodystrophy therapy.
[x-linked adrenoleukodystrophy]
X-
linked
adrenoleukodystrophy
(
X-
ALD
)
is
a
peroxisomal
disorder
caused
by
mutations
in
the
ABCD
1
gene
that
encodes
the
peroxisomal
ATP-binding
cassette
(
ABC
)
transporter
subfamily
D
member
1
protein
(
ABCD
1
)
,
which
is
referred
to
as
the
adrenoleukodystrophy
protein
(
ALDP
)
.
Induction
of
the
ABCD
2
gene
,
the
closest
homolog
of
ABCD
1
,
has
been
mentioned
as
a
possible
therapeutic
option
for
the
defective
ABCD
1
protein
in
X-
ALD
.
However
,
little
is
known
about
the
transcriptional
regulation
of
ABCD
2
gene
expression
.
Here
,
through
in
silico
analysis
,
we
found
two
putative
TCF-
4
binding
elements
between
nucleotide
positions
-
360
and
-
260
of
the
promoter
region
of
the
ABCD
2
gene
.
The
transcriptional
activity
of
the
ABCD
2
promoter
was
strongly
increased
by
ectopic
expression
of
β-catenin
and
TCF-
4
.
In
addition
,
mutation
of
either
or
both
TCF-
4
binding
elements
by
site-directed
mutagenesis
decreased
promoter
activity
.
This
was
further
validated
by
the
finding
that
β-catenin
and
the
promoter
of
the
ABCD
2
gene
were
pulled
down
with
a
β-catenin
antibody
in
a
chromatin
immunoprecipitation
assay
.
Moreover
,
real-time
PCR
analysis
revealed
that
β-catenin
and
TCF-
4
increased
mRNA
levels
of
ABCD
2
in
both
a
hepatocellular
carcinoma
cell
line
and
primary
fibroblasts
from
an
X-
ALD
patient
.
Interestingly
,
we
found
that
the
levels
of
very
long
chain
fatty
acids
were
decreased
by
ectopic
expression
of
ABCD
2
-
GFP
as
well
as
β-catenin
and
TCF-
4
.
Taken
together
,
our
results
demonstrate
for
the
first
time
the
direct
regulation
of
ABCD
2
by
β-catenin
and
TCF-
4
.
Diseases
Validation
Diseases presenting
"hepatocellular carcinoma"
symptom
cholangiocarcinoma
erythropoietic protoporphyria
esophageal adenocarcinoma
esophageal squamous cell carcinoma
primary hyperoxaluria type 1
severe combined immunodeficiency
werner syndrome
x-linked adrenoleukodystrophy
This symptom has already been validated
