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Rapamycin-insensitive up-regulation of adipocyte phospholipase A2 in tuberous sclerosis and lymphangioleiomyomatosis.
[lymphangioleiomyomatosis]
Tuberous
sclerosis
syndrome
(
TSC
)
is
an
autosomal
dominant
tumor
suppressor
gene
syndrome
affecting
multiple
organs
,
including
renal
angiomyolipomas
and
pulmonary
lymphangioleiomyomatosis
(
LAM
)
.
LAM
is
a
female
-predominant
interstitial
lung
disease
characterized
by
the
progressive
cyst
formation
and
respiratory
failure
,
which
is
also
seen
in
sporadic
patients
without
TSC
.
Mutations
in
TSC
1
or
TSC
2
cause
TSC
,
result
in
hyperactivation
of
mammalian
target
of
rapamycin
(
mTOR
)
,
and
are
also
seen
in
LAM
cells
in
sporadic
LAM
.
We
recently
reported
that
prostaglandin
biosynthesis
and
cyclooxygenase-
2
were
deregulated
in
TSC
and
LAM
.
Phospholipase
A
2
(
PLA
2
)
is
the
rate-limiting
enzyme
that
catalyzes
the
conversion
of
plasma
membrane
phospholipids
into
prostaglandins
.
In
this
study
,
we
identified
upregulation
of
adipocyte
AdPLA
2
(
PLA
2
G
16
)
in
LAM
nodule
cells
using
publicly
available
expression
data
.
We
showed
that
the
levels
of
AdPLA
2
transcript
and
protein
were
higher
in
LAM
lungs
compared
with
control
lungs
.
We
then
showed
that
TSC
2
negatively
regulates
the
expression
of
AdPLA
2
,
and
loss
of
TSC
2
is
associated
with
elevated
production
of
prostaglandin
E
2
(
PGE
2
)
and
prostacyclin
(
PGI
2
)
in
cell
culture
models
.
Mouse
model
studies
also
showed
increased
expression
of
AdPLA
2
in
xenograft
tumors
,
estrogen-induced
lung
metastatic
lesions
of
Tsc
2
null
leiomyoma-derived
cells
,
and
spontaneous
renal
cystadenomas
from
Tsc
2
+
/
-
mice
.
Importantly
,
rapamycin
treatment
did
not
affect
the
expression
of
AdPLA
2
and
the
production
of
PGE
2
by
TSC
2
-
deficient
mouse
embryonic
fibroblast
(
Tsc
2
-
/
-
MEFs
)
,
rat
uterine
leiomyoma
-derived
ELT
3
cells
,
and
LAM
patient-associated
renal
angiomyolipoma
-derived
"
mesenchymal
"
cells
.
Furthermore
,
methyl
arachidonyl
fluorophosphate
(
MAFP
)
,
a
potent
irreversible
PLA
2
inhibitor
,
selectively
suppressed
the
growth
and
induced
apoptosis
of
TSC
2
-
deficient
LAM
patient-derived
cells
relative
to
TSC
2
-
addback
cells
.
Our
findings
suggest
that
AdPLA
2
plays
an
important
role
in
promoting
tumorigenesis
and
disease
progression
by
modulating
the
production
of
prostaglandins
and
may
serve
as
a
potential
therapeutic
target
in
TSC
and
LAM
.
Diseases
Validation
Diseases presenting
"deficient mouse"
symptom
benign recurrent intrahepatic cholestasis
lymphangioleiomyomatosis
werner syndrome
zellweger syndrome
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