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A random Abstract
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Loss of p16(Ink4a) Function Rescues Cellular Senescence Induced by Telomere Dysfunction.
[werner syndrome]
p
16
(
Ink
4
a
)
is
a
tumor
suppressor
and
a
marker
for
cellular
senescence
.
Previous
studies
have
shown
that
p
16
(
Ink
4
a
)
plays
an
important
role
in
the
response
to
DNA
damage
signals
caused
by
telomere
dysfunction
.
In
this
study
,
we
crossed
Wrn
(
-
/
-
)
and
p
16
(
Ink
4
a-
/
-
)
mice
to
knock
out
the
p
16
(
Ink
4
a
)
function
in
a
Wrn
null
background
.
Growth
curves
showed
that
loss
of
p
16
(
Ink
4
a
)
could
rescue
the
growth
barriers
that
are
observed
in
Wrn
(
-
/
-
)
mouse
embryonic
fibroblasts
(
MEFs
)
.
By
challenging
the
MEFs
with
the
global
genotoxin
doxorubicin
,
we
showed
that
loss
of
p
16
(
Ink
4
a
)
did
not
dramatically
affect
the
global
DNA
damage
response
of
Wrn
(
-
/
-
)
MEFs
induced
by
doxorubicin
.
However
,
in
response
to
telomere
dysfunction
initiated
by
the
telomere
damaging
protein
TRF
2
(
ΔBΔM
)
,
loss
of
p
16
(
Ink
4
a
)
could
partially
overcome
the
DNA
damage
response
by
disabling
p
16
(
Ink
4
a
)
up-regulation
and
reducing
the
accumulation
of
γ-
H
2
AX
that
is
observed
in
Wrn
(
-
/
-
)
MEFs
.
Furthermore
,
in
response
to
TRF
2
(
ΔBΔM
)
overexpression
,
Wrn
(
-
/
-
)
MEFs
senesced
within
several
passages
.
In
contrast
,
p
16
(
Ink
4
a-
/
-
)
and
p
16
(
Ink
4
a-
/
-
)
Wrn
(
-
/
-
)
MEFs
could
continuously
grow
and
lose
expression
of
the
exogenous
TRF
2
(
ΔBΔM
)
in
their
late
passages
.
In
summary
,
our
data
suggest
that
in
the
context
of
telomere
dysfunction
,
loss
of
p
16
(
Ink
4
a
)
function
could
prevent
cells
from
senescence
.
These
results
shed
light
on
the
anti-aging
strategy
through
regulation
of
p
16
(
Ink
4
a
)
expression
.
