Journal of Proteome Research,
Год журнала:
2023,
Номер
22(12), С. 3773 - 3779
Опубликована: Ноя. 1, 2023
Accurate
measurements
of
the
molecular
composition
single
cells
will
be
necessary
for
understanding
relationship
between
gene
expression
and
function
in
diverse
cell
types.
One
most
important
phenotypes
that
differs
is
their
size,
which
was
recently
shown
to
an
determinant
proteome
populations
similarly
sized
cells.
We,
therefore,
sought
test
if
effects
size
on
protein
concentrations
were
also
evident
single-cell
proteomics
data.
Using
relative
a
set
reference
proteins
estimate
cell's
DNA-to-cell
volume
ratio,
we
found
differences
explain
significant
amount
cell-to-cell
variance
two
published
data
sets.
Proceedings of the National Academy of Sciences,
Год журнала:
2023,
Номер
120(39)
Опубликована: Сен. 18, 2023
Cell
size
and
cell
count
are
adaptively
regulated
intimately
linked
to
growth
function.
Yet,
despite
their
widespread
relevance,
the
relation
between
has
never
been
formally
examined
over
whole
human
body.
Here,
we
compile
a
comprehensive
dataset
of
all
major
types,
with
data
drawn
from
>1,500
published
sources.
We
consider
body
representative
male
(70
kg),
which
allows
further
estimates
female
(60
kg)
10-y-old
child
(32
kg).
build
hierarchical
interface
for
cellular
organization
body,
giving
easy
access
data,
methods,
sources
(https://humancelltreemap.mis.mpg.de/).
In
total,
estimate
total
counts
≈36
trillion
cells
in
male,
≈28
female,
≈17
child.
These
reveal
surprising
inverse
count,
implying
trade-off
these
variables,
such
that
within
given
logarithmic
class
contribute
an
equal
fraction
body's
biomass.
also
find
coefficient
variation
is
approximately
independent
mean
size,
existence
cell-size
regulation
across
types.
Our
serve
establish
holistic
quantitative
framework
highlight
large-scale
patterns
biology.
Molecular Cell,
Год журнала:
2023,
Номер
83(22), С. 4062 - 4077.e5
Опубликована: Ноя. 1, 2023
Abnormal
increases
in
cell
size
are
associated
with
senescence
and
cycle
exit.
The
mechanisms
by
which
overgrowth
primes
cells
to
withdraw
from
the
remain
unknown.
We
address
this
question
using
CDK4/6
inhibitors,
arrest
G0/G1
licensed
treat
advanced
HR+/HER2-
breast
cancer.
demonstrate
that
CDK4/6-inhibited
overgrow
during
G0/G1,
causing
p38/p53/p21-dependent
withdrawal.
Cell
withdrawal
is
triggered
biphasic
p21
induction.
first
wave
caused
osmotic
stress,
leading
p38-
size-dependent
accumulation
of
p21.
inhibitor
washout
results
some
entering
S-phase.
Overgrown
experience
replication
resulting
a
second
promotes
G2
or
subsequent
G1.
propose
levels
integrate
signals
overgrowth-triggered
stresses
determine
fate.
This
model
explains
how
hypertrophy
can
drive
why
inhibitors
have
long-lasting
effects
patients.
PLoS Biology,
Год журнала:
2024,
Номер
22(1), С. e3002453 - e3002453
Опубликована: Янв. 5, 2024
To
achieve
a
stable
size
distribution
over
multiple
generations,
proliferating
cells
require
means
of
counteracting
stochastic
noise
in
the
rate
growth,
time
spent
various
phases
cell
cycle,
and
imprecision
placement
plane
division.
In
most
widely
accepted
model,
is
thought
to
be
regulated
at
G1/S
transition,
such
that
smaller
than
critical
pause
end
G1
phase
until
they
have
accumulated
mass
predetermined
threshold,
which
point
proceed
through
rest
cycle.
However,
based
solely
on
specific
checkpoint
G1/S,
cannot
readily
explain
why
with
deficient
control
mechanisms
are
still
able
maintain
very
distribution.
Furthermore,
model
would
not
easily
account
for
variation
during
subsequent
anticipated
G1/S.
address
questions,
we
applied
computationally
enhanced
quantitative
microscopy
(ceQPM)
populations
cultured
human
lines,
enables
highly
accurate
measurement
dry
individual
throughout
From
these
measurements,
evaluated
factors
contribute
maintaining
homeostasis
any
Our
findings
reveal
accurately
maintained,
despite
disruptions
normal
machinery
or
perturbations
growth.
Control
generally
confined
regulation
length.
Instead
imposed
lines
examined,
find
coefficient
(CV)
population
begins
decline
well
before
transition
continues
S
G2
phases.
Among
different
types
tested,
detailed
response
growth
differs.
general,
when
it
falls
below
exponential
natural
increase
CV
effectively
constrained.
We
both
mass-dependent
cycle
modulation
reducing
within
population.
Through
interplay
coordination
2
processes,
emerges.
Such
previously
unappreciated
general
principles
cells.
These
same
regulatory
processes
might
also
operative
terminally
differentiated
Further
dynamical
studies
should
lead
better
understanding
underlying
molecular
control.
Cell Death and Disease,
Год журнала:
2025,
Номер
16(1)
Опубликована: Янв. 3, 2025
Abstract
Aging
of
the
brain
vasculature
plays
a
key
role
in
development
neurovascular
and
neurodegenerative
diseases,
thereby
contributing
to
cognitive
impairment.
Among
other
factors,
DNA
damage
strongly
promotes
cellular
aging,
however,
genomic
instability
endothelial
cells
(EC)
its
potential
effect
on
homeostasis
is
still
largely
unclear.
We
here
investigated
how
aging
impacts
blood-brain
barrier
(BBB)
function
by
using
excision
repair
cross
complementation
group
1
(ERCC1)-deficient
human
ECs
an
EC-specific
Ercc1
knock
out
(EC-KO)
mouse
model.
In
vitro,
ERCC1-deficient
displayed
increased
senescence-associated
secretory
phenotype
expression,
reduced
BBB
integrity,
higher
sprouting
capacities
due
underlying
dysregulation
Dll4-Notch
pathway.
line,
EC-KO
mice
showed
more
P21
+
cells,
augmented
expression
angiogenic
markers,
concomitant
increase
number
pericytes.
Moreover,
leakage
enhanced
cell
adhesion
molecule
accompanied
peripheral
immune
infiltration
into
brain.
These
findings
were
confined
white
matter,
suggesting
regional
susceptibility.
Collectively,
our
results
underline
as
driver
impaired
function,
sprouting,
migration
brain,
observed
during
process.
Molecular Cell,
Год журнала:
2023,
Номер
83(22), С. 4032 - 4046.e6
Опубликована: Ноя. 1, 2023
Cellular
senescence
refers
to
an
irreversible
state
of
cell-cycle
arrest
and
plays
important
roles
in
aging
cancer
biology.
Because
is
associated
with
increased
cell
size,
we
used
reversible
arrests
combined
growth
rate
modulation
study
how
excessive
affects
proliferation.
We
find
that
enlarged
cells
upregulate
p21,
which
limits
progression.
Cells
re-enter
the
cycle
encounter
replication
stress
well
tolerated
physiologically
sized
but
causes
severe
DNA
damage
cells,
ultimately
resulting
mitotic
failure
permanent
withdrawal.
demonstrate
fail
recruit
53BP1
other
non-homologous
end
joining
(NHEJ)
machinery
sites
robustly
initiate
damage-dependent
p53
signaling,
rendering
them
highly
sensitive
genotoxic
stress.
propose
impaired
response
primes
for
persistent
replication-acquired
damage,
leading
division
exit.
Molecular Cell,
Год журнала:
2023,
Номер
83(22), С. 4047 - 4061.e6
Опубликована: Ноя. 1, 2023
CDK4/6
inhibitors
are
remarkable
anti-cancer
drugs
that
can
arrest
tumor
cells
in
G1
and
induce
their
senescence
while
causing
only
relatively
mild
toxicities
healthy
tissues.
How
they
achieve
this
mechanistically
is
unclear.
We
show
here
specifically
vulnerable
to
inhibition
because
during
the
arrest,
oncogenic
signals
drive
toxic
cell
overgrowth.
This
overgrowth
causes
permanent
cycle
withdrawal
by
either
preventing
progression
from
or
inducing
genotoxic
damage
subsequent
S-phase
mitosis.
Inhibiting
reverting
converge
onto
mTOR
rescue
excessive
growth,
DNA
damage,
exit
cancer
cells.
Conversely,
non-transformed
these
phenotypes
sensitize
inhibition.
Together,
demonstrates
growth
a
synthetic
lethal
combination
exploited
tumor-specific
toxicity.
Molecular Cell,
Год журнала:
2023,
Номер
83(22), С. 4078 - 4092.e6
Опубликована: Ноя. 1, 2023
Tumor
growth
is
driven
by
continued
cellular
and
proliferation.
Cyclin-dependent
kinase
7's
(CDK7)
role
in
activating
mitotic
CDKs
global
gene
expression
makes
it
therefore
an
attractive
target
for
cancer
therapies.
However,
what
cells
particularly
sensitive
to
CDK7
inhibition
(CDK7i)
remains
unclear.Here,
we
address
this
question.
We
show
that
CDK7i,
samuraciclib,
induces
a
permanent
cell-cycle
exit,
known
as
senescence,
without
promoting
DNA
damage
signaling
or
cell
death.
A
chemogenetic
genome-wide
CRISPR
knockout
screen
identified
active
mTOR
(mammalian
of
rapamycin)
promotes
samuraciclib-induced
senescence.
decreases
samuraciclib
sensitivity,
increased
mTOR-dependent
correlates
with
sensitivity
lines.
Reverting
growth-promoting
mutation
PIK3CA
wild
type
CDK7i.
Our
work
establishes
enhanced
alone
CDK7i
providing
explanation
why
some
cancers
are
more
CDK
than
normally
growing
cells.
Nature Communications,
Год журнала:
2023,
Номер
14(1)
Опубликована: Июль 27, 2023
Abstract
Senescence,
a
state
of
irreversible
cell-cycle
withdrawal,
is
difficult
to
distinguish
from
quiescence,
reversible
withdrawal.
This
difficulty
arises
because
quiescent
and
senescent
cells
are
defined
by
overlapping
biomarkers,
raising
the
question
whether
these
states
truly
distinct.
To
address
this,
we
use
single-cell
time-lapse
imaging
slow-cycling
that
spend
long
periods
in
quiescence
never
cycle
after
recovery
senescence-inducing
treatments,
followed
staining
for
various
senescence
biomarkers.
We
find
intensity
multiple
biomarkers
graded
rather
than
binary
reflects
duration
per
se.
Together,
our
data
show
apparent
nearly
molecularly
indistinguishable
each
other
at
snapshot
time.
suggests
withdrawal
itself
binary,
where
intensities
integrate
past
Developmental Cell,
Год журнала:
2023,
Номер
58(16), С. 1462 - 1476.e8
Опубликована: Июнь 19, 2023
Cell
proliferation
is
a
central
process
in
tissue
development,
homeostasis,
and
disease,
yet
how
regulated
the
context
remains
poorly
understood.
Here,
we
introduce
quantitative
framework
to
elucidate
growth
dynamics
regulate
cell
proliferation.
Using
MDCK
epithelial
monolayers,
show
that
limiting
rate
of
expansion
creates
confinement
suppresses
growth;
however,
this
does
not
directly
affect
cycle.
This
leads
uncoupling
between
rates
division
epithelia
and,
thereby,
reduces
volume.
Division
becomes
arrested
at
minimal
volume,
which
consistent
across
diverse
vivo.
nucleus
approaches
minimum
volume
capable
packaging
genome.
Loss
cyclin
D1-dependent
cell-volume
regulation
results
an
abnormally
high
nuclear-to-cytoplasmic
ratio
DNA
damage.
Overall,
demonstrate
by
interplay
regulation.