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PTEN lipid phosphatase activity and proper subcellular localization are necessary and sufficient for down-regulating AKT phosphorylation in the nucleus in Cowden syndrome.
[cowden syndrome]
Germline
mutations
in
PTEN
are
associated
with
phosphatase
and
tensin
homolog
deleted
on
chromosome
10
(
PTEN
)
hamartoma
tumor
syndrome
including
Cowden
syndrome
(
CS
)
and
Cowden
-like
syndrome
(
CSL
)
that
predisposes
to
high
risks
of
benign
and
malignant
tumors
of
thyroid
and
breast
.
The
objective
of
the
study
was
to
analyze
the
subcellular
pattern
of
phosphorylated
(
P
)
-
AKT
expression
in
nonmedullary
thyroid
cancers
from
PTEN
hamartoma
tumor
syndrome
patients
and
to
investigate
whether
the
lack
of
PTEN
in
the
nucleus
and
/
or
lack
of
proper
PTEN
function
in
the
nucleus
affect
(
s
)
nuclear
AKT
activity
in
CS
patients
.
In
all
,
664
patients
with
CS
/
CSL
were
screened
for
PTEN
germline
mutations
and
nonmedullary
thyroid
cancers
.
Twenty
-
two
patients
who
have
both
pathogenic
PTEN
germline
mutations
and
nonmedullary
thyroid
cancers
were
selected
.
Thyroid
samples
from
these
patients
were
stained
for
PTEN
and
P-AKT
.
In
our
in
vitro
study
,
PTEN
was
knocked
down
or
overexpressed
in
both
thyroid
cancer
cells
and
breast
cancer
cells
,
and
nuclear
P-AKT
was
compared
with
the
control
.
Loss
of
PTEN
protein
was
found
in
thyroid
adenomas
and
carcinomas
from
all
22
(
100
%
)
PTEN
(
Mut
+
)
CS
/
CSL
patients
.
AKT
activation
was
identified
in
17
of
22
(
77
.
3
%
)
thyroid
adenoma
/
carcinoma
specimens
,
and
most
patients
(
63
.
7
%
)
have
activated
nuclear
AKT
.
Knockdown
of
PTEN
in
cells
containing
wild-
type
PTEN
enhanced
nuclear
P-AKT
,
whereas
expression
of
wild-
type
PTEN
,
but
not
phosphatase-dead
mutants
(
C
124
S
or
G
129
E
)
,
markedly
reduced
nuclear
P-AKT
in
PTEN
null
cells
.
We
also
showed
that
in
breast
cancer
but
not
thyroid
cancer
cells
,
PTEN
suppresses
nuclear
P-AKT
mainly
through
decreasing
P-AKT
nuclear
translocation
by
reducing
the
PIP
3
/
P-AKT
reservoir
in
the
cytoplasm
.
In
thyroid
cancer
cells
,
PTEN
suppresses
phosphorylation
of
AKT
already
resident
in
the
nucleus
.
PTEN
is
necessary
and
sufficient
for
inhibiting
AKT
activation
in
the
nucleus
through
its
intact
lipid
phosphatase
activity
and
proper
subcellular
localization
.
Diseases
Validation
Diseases presenting
"tensin homolog deleted on chromosome 10"
symptom
cowden syndrome
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