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Cowden syndrome-associated germline SDHD variants alter PTEN nuclear translocation through SRC-induced PTEN oxidation.
[cowden syndrome]
Germline
mutations
in
the
PTEN
tumor
-suppressor
gene
and
germline
variations
in
succinate
dehydrogenase
subunit
D
gene
(
SDHD
-G
12
S
,
SDHD
-H
50
R
)
are
associated
with
a
subset
of
Cowden
syndrome
and
Cowden
syndrome
-like
individuals
(
CS
/
CSL
)
and
confer
high
risk
of
breast
,
thyroid
and
other
cancers
.
However
,
very
little
is
known
about
the
underlying
crosstalk
between
SDHD
and
PTEN
in
CS
-associated
thyroid
cancer
.
Here
,
we
show
SDHD
-G
12
S
and
SDHD
-H
50
R
lead
to
impaired
PTEN
function
through
alteration
of
its
subcellular
localization
accompanied
by
resistance
to
apoptosis
and
induction
of
migration
in
both
papillary
and
follicular
thyroid
carcinoma
cell
lines
.
Other
studies
have
shown
elevated
proto-oncogene
tyrosine
kinase
(
SRC
)
activity
in
invasive
thyroid
cancer
cells
;
so
,
we
explore
bosutinib
,
a
specific
inhibitor
for
SRC
,
to
explore
SRC
as
a
mediator
of
SDH-
PTEN
crosstalk
in
this
context
.
We
show
that
SRC
inhibition
could
rescue
SDHD
dysfunction-induced
cellular
phenotype
and
tumorigenesis
only
when
wild-
type
PTEN
is
expressed
,
in
thyroid
cancer
lines
.
Patient
lymphoblast
cells
carrying
either
SDHD
-G
12
S
or
SDHD
-H
50
R
also
show
increased
nuclear
PTEN
and
more
oxidized
PTEN
after
hydrogen
peroxide
treatment
.
Like
in
thyroid
cells
,
bosutinib
decreases
oxidative
PTEN
in
patient
lymphoblast
cells
carrying
SDHD
variants
,
but
not
in
patients
carrying
both
SDHD
variants
and
PTEN
truncating
mutations
.
In
summary
,
our
data
suggest
a
novel
mechanism
whereby
SDHD
germline
variants
SDHD
-G
12
S
or
SDHD
-H
50
R
induce
thyroid
tumorigenesis
mediated
by
PTEN
accumulation
in
the
nucleus
and
may
shed
light
on
potential
treatment
with
SRC
inhibitors
like
bosutinib
in
PTEN
-wild-
type
SDHD
-variant
/
mutation
positive
CS
/
CSL
patients
and
sporadic
thyroid
neoplasias
.
Diseases
Validation
Diseases presenting
"cancer"
symptom
achondroplasia
acute rheumatic fever
adrenal incidentaloma
alpha-thalassemia
benign recurrent intrahepatic cholestasis
cadasil
canavan disease
carcinoma of the gallbladder
cholangiocarcinoma
coats disease
congenital adrenal hyperplasia
congenital diaphragmatic hernia
cowden syndrome
cushing syndrome
cutaneous mastocytosis
dedifferentiated liposarcoma
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
erdheim-chester disease
erythropoietic protoporphyria
esophageal adenocarcinoma
esophageal carcinoma
esophageal squamous cell carcinoma
familial hypocalciuric hypercalcemia
familial mediterranean fever
gm1 gangliosidosis
heparin-induced thrombocytopenia
hereditary cerebral hemorrhage with amyloidosis
hirschsprung disease
hodgkin lymphoma, classical
inclusion body myositis
junctional epidermolysis bullosa
kabuki syndrome
kallmann syndrome
kindler syndrome
lamellar ichthyosis
liposarcoma
locked-in syndrome
lymphangioleiomyomatosis
monosomy 21
neuralgic amyotrophy
oculocutaneous albinism
oligodontia
oral submucous fibrosis
papillon-lefèvre syndrome
pendred syndrome
pleomorphic liposarcoma
primary effusion lymphoma
proteus syndrome
pyomyositis
pyruvate dehydrogenase deficiency
severe combined immunodeficiency
sneddon syndrome
systemic capillary leak syndrome
triple a syndrome
von hippel-lindau disease
waldenström macroglobulinemia
well-differentiated liposarcoma
werner syndrome
wiskott-aldrich syndrome
wolf-hirschhorn syndrome
x-linked adrenoleukodystrophy
This symptom has already been validated