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Imbalance of intermediate filament component keratin 14 contributes to increased stress signalling in epidermolysis bullosa simplex.
[epidermolysis bullosa simplex]
An
important
characteristic
of
epidermolysis
bullosa
simplex
Dowling-
Meara
(
EBS
-
DM
)
keratinocytes
is
the
increased
level
of
Jun
N-
terminal
kinase
(
JNK
)
stress
signalling
,
which
is
thought
to
contribute
to
the
disease
phenotype
.
In
this
work
,
we
report
on
the
dramatic
up-regulation
of
cytokeratin
14
(
K
14
)
in
the
EBS
-
DM
model
cell
line
KEB
7
at
both
the
transcriptional
and
translational
levels
,
which
is
noteworthy
because
KEB
7
patient
cells
are
heterozygous
for
a
missense
mutation
(
R
125
P
)
in
K
14
.
By
performing
functional
assays
,
we
show
a
direct
link
between
overexpressed
wild-
type
K
14
and
increased
JNK
signalling
in
healthy
,
immortalized
keratinocytes
.
This
observation
led
us
to
hypothesize
a
positive
feedback
model
in
which
mutant
(
R
125
P
)
K
14
triggers
JNK
signalling
,
leading
to
increased
AP
1
-
dependent
expression
of
K
14
,
which
in
turn
amplifies
JNK
signalling
further
.
We
therefore
suggest
that
an
imbalance
of
cytoplasmic
K
14
monomers
and
K
14
incorporated
into
the
intermediate
filament
(
IF
)
network
leads
to
elevated
stress
signalling
,
potentially
altering
IF
dynamics
by
phosphorylation
,
which
as
a
side
effect
,
weakens
EBS
-
DM
keratinocytes
.
Diseases
Validation
Diseases presenting
"increased level of jun n-terminal kinase"
symptom
epidermolysis bullosa simplex
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