Exploring the role of Kindlin-1 in skin homeostasis and squamous cell carcinoma
dc.contributor.advisor
Brunton, Valerie
en
dc.contributor.advisor
Frame, Margaret
en
dc.contributor.author
Stavrou, Ifigeneia
en
dc.contributor.sponsor
Medical Research Council (MRC)
en
dc.date.accessioned
2018-08-21T09:58:56Z
dc.date.available
2018-08-21T09:58:56Z
dc.date.issued
2017-07-08
dc.description.abstract
Kindlin-1
(Kin1)
is
an
epithelial
focal
adhesion
protein
that
plays
a
key
role
in
integrin-mediated
anchorage
of
cells
to
the
extracellular
matrix.
Congenital
loss
of
Kin1
leads
to
Kindler
Syndrome
(KS),
whose
symptoms
include
progressive
epidermal
atrophy,
reduced
keratinocyte
proliferation,
skin
blistering
and
increased
incidence
of
aggressive
Squamous
Cell
Carcinoma
(SCC).
Objectives
of
this
study
were
to
examine
the
role
of
Kin1
in
skin
homeostasis
and
in
the
development
of
aggressive
SCC
in
KS,
as
the
molecular
aetiologies
for
these
pathologies
are
yet
to
be
clearly
understood.
We
first
examined
whether
the
recently
discovered
role
of
Kin1
in
mitosis
contributes
to
reduced
keratinocyte
proliferation
observed
in
KS
epidermis.
We
discovered
that
short-‐term
loss
of
Kin1
in
adult
mouse
epidermis
reduced
keratinocyte
proliferation.
We
also
found
that
Kin1
loss
increased
mitotic
spindle
misorientation
that,
according
to
the
model
of
cell
division
in
skin
homeostasis,
decreases
cell
proliferative
potential,
and,
thus,
may
account
for
the
reduced
proliferation
in
our
model.
As
spindle
misorientation
can
stem
from
microtubule
instability,
we
believe
that
the
reduction
in
acetylated
α-
tubulin
(ac-tub),
a
known
marker
of
stable
microtubules,
that
we
also
observed
in
mouse
epidermis
following
Kin1
loss
could
account
for
the
defective
spindle
orientation
phenotype.
The
role
of
Kin1
in
spindle
orientation
was
also
evident
in
vitro.
Moreover,
data
from
our
lab
revealed
showed
reduction
in
spindle
ac-tub
following
Kin1
depletion,
mirroring
our
in
vivo
observation.
Additionally
to
orientation
defects,
in
vitro
depletion
of
Kin1
led
to
enhanced
chromosome
missegregation,
which
is
likely
to
result
from
reduced
microtubule
stability
due
to
low
levels
of
ac-tub.
We
showed
that
role
of
Kin1
in
spindle
orientation
and
chromosome
segregation
is
dependent
on
HDAC6,
a
known
inhibitor
of
ac-tub.
Overall,
our
results
uncover
an
in
vitro
and
in
vivo
role
of
Kin1
in
mitotic
spindle
fidelity
that
could
be
crucial
to
skin
homeostasis,
and,
when
disturbed,
may
lead
to
reduced
keratinocyte
proliferation.
Interestingly,
our
in
vitro
studies
also
revealed
that
in
mitosis
Kin1
and
Kindlin-2
(Kin2)
had
overlapping,
but
also
distinct
roles,
which
is
in
line
with
various
reports
that
show
different
biological
functions
for
the
two
protein
isoforms.
Our
next
and
final
aim
was
to
explore
the
roles
of
Kin1
in
the
development
and
progression
of
SCC,
which
would
help
us
comprehend
the
reason
behind
the
cancer’s
aggressive
nature
in
KS.
By
employing
in
vitro
and
in
vivo
SCC
growth
assays
and
tumour
immunohistochemical
staining
we
found
that
absence
of
Kin1
in
SCC
cells
and
tumours
enhanced
proliferation
and
growth,
and
enhanced
tumour
vascularisation.
RNA
sequencing
of
tumour
material
revealed
that
lack
of
Kin1
increased
expression
of
matrix
metalloproteinases
and
chemokines,
which
have
been
implicated
in
tumour
progression
via
promotion
of
angiogenesis
and
invasion
in
a
plethora
of
studies,
and
of
various
angiogenesis
markers.
Together
this
provides
an
insight
into
the
mechanisms
via
which
Kin1
controls
tumour
microenvironment
and,
ultimately,
SCC
tumour
growth
and
development.
Overall,
we
report
an
in
vitro
and
in
vivo
role
for
Kin1
in
mitotic
spindle
stability,
which
affects
a
variety
of
mitotic
processes
and
may
be
linked
to
reduced
keratinocyte
proliferation
observed
in
epidermis
of
KS
patients,
thus
contributing
to
skin
homeostasis.
Moreover,
we
describe
a
role
for
Kin1
in
regulation
of
SCC
tumour
growth
and
progression,
which
may
ultimately
offer
an
explanation
for
the
aggressive
and
life‐threatening
nature
of
SCC
developed
in
KS.
en
dc.identifier.uri
http://hdl.handle.net/1842/31466
dc.language.iso
en
dc.publisher
The University of Edinburgh
en
dc.relation.hasversion
Patel, H., Stavrou, I., Shrestha, R.L., Draviam, V., Frame, M.C., Brunton, V.G. (2016). Kindlin1 regulates microtubule function to ensure normal mitosis. Journal of Molecular and Cell Biology 8, 338-‐348
en
dc.subject
Kindler Syndrome
en
dc.subject
Squamous Cell Carcinoma
en
dc.subject
Kindlin-1
en
dc.subject
Kin1
en
dc.subject
mitosis
en
dc.subject
chemokines
en
dc.title
Exploring the role of Kindlin-1 in skin homeostasis and squamous cell carcinoma
en
dc.type
Thesis or Dissertation
en
dc.type.qualificationlevel
Doctoral
en
dc.type.qualificationname
PhD Doctor of Philosophy
en
Files
Original bundle
1 - 1 of 1
- Name:
- Stavrou2017.pdf
- Size:
- 51.38 MB
- Format:
- Adobe Portable Document Format
This item appears in the following Collection(s)