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Induction of senescence pathways in Kindler syndrome primary keratinocytes.
[kindler syndrome]
Individuals
with
Kindler
syndrome
(
KS
)
have
loss
-of-function
mutations
in
the
FERMT
1
gene
that
encodes
the
focal
adhesion
component
kindlin-
1
.
The
major
clinical
manifestation
of
KS
is
epidermal
atrophy
(
premature
skin
ageing
)
.
This
phenotypic
feature
is
thought
to
be
related
to
the
decreased
proliferation
rate
of
KS
keratinocytes
;
nevertheless
,
molecular
mediators
of
such
abnormal
behaviour
have
not
been
fully
elucidated
.
To
investigate
how
kindlin-
1
deficiency
affects
the
proliferative
potential
of
primary
human
keratinocytes
.
We
serially
cultivated
nine
primary
KS
keratinocyte
strains
until
senescence
and
determined
their
lifespan
and
colony-forming
efficiency
(
CFE
)
at
each
serial
passage
.
The
expression
of
molecular
markers
of
stemness
and
cellular
senescence
were
investigated
by
immunoblotting
using
cell
extracts
of
primary
keratinocyte
cultures
from
patients
with
KS
and
healthy
donors
.
In
another
set
of
experiments
,
kindlin-
1
downregulation
in
normal
keratinocytes
was
obtained
by
small
interfering
RNA
(
siRNA
)
technology
.
We
found
that
KS
keratinocytes
exhibited
a
precocious
senescence
and
strongly
reduced
clonogenic
potential
.
Moreover
,
KS
cultures
showed
a
strikingly
increased
percentage
of
aborted
colonies
(
paraclones
)
already
at
early
passages
indicating
an
early
depletion
of
stem
cells
.
Immunoblotting
analysis
of
KS
keratinocyte
extracts
showed
reduced
levels
of
the
stemness
markers
p
63
and
Bmi-
1
,
upregulation
of
p
16
and
scant
amounts
of
hypophosphorylated
Rb
protein
,
which
indicated
cell
cycle-arrested
status
.
Treatment
of
normal
human
primary
keratinocytes
with
siRNA
targeting
kindlin-
1
proved
that
its
deficiency
was
directly
responsible
for
p
63
,
Bmi-
1
and
pRb
downregulation
and
p
16
induction
.
Our
data
directly
implicate
kindlin-
1
in
preventing
premature
senescence
of
keratinocytes
.
Diseases
Validation
Diseases presenting
"an early depletion of stem cells"
symptom
kindler syndrome
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