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Integration of mTOR and estrogen-ERK2 signaling in lymphangioleiomyomatosis pathogenesis.
[lymphangioleiomyomatosis]
Lymphangioleiomyomatosis
(
LAM
)
is
a
destructive
lung
disease
of
women
associated
with
the
metastasis
of
tuberin-null
cells
with
hyperactive
mammalian
target
of
rapamycin
complex
1
(
mTORC
1
)
activity
.
Clinical
trials
with
the
mTORC
1
inhibitor
rapamycin
have
revealed
partial
efficacy
but
are
not
curative
.
Pregnancy
appears
to
exacerbate
LAM
,
suggesting
that
estrogen
(
E
2
)
may
play
a
role
in
the
unique
features
of
LAM
.
Using
a
LAM
patient-derived
cell
line
(
bearing
biallelic
Tuberin
inactivation
)
,
we
demonstrate
that
E
2
stimulates
a
robust
and
biphasic
activation
of
ERK
2
and
transcription
of
the
late
response-
gene
Fra
1
associated
with
epithelial-
to
-mesenchymal
transition
.
In
a
carefully
orchestrated
collaboration
,
activated
mTORC
1
/
S
6
K
1
signaling
enhances
the
efficiency
of
Fra
1
translation
of
Fra
1
mRNA
transcribed
by
the
E
2
-
ERK
2
pathway
,
through
the
phosphorylation
of
the
S
6
K
1
-
dependent
eukaryotic
translation
initiation
factor
4
B
.
Our
results
indicate
that
targeting
the
E
2
-
ERK
pathway
in
combination
with
the
mTORC
1
pathway
may
be
an
effective
combination
therapy
for
LAM
.
Diseases
Validation
Diseases presenting
"hyperactive mammalian target"
symptom
lymphangioleiomyomatosis
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