International Journal of Biological Sciences,
Год журнала:
2024,
Номер
21(2), С. 758 - 771
Опубликована: Дек. 31, 2024
Bladder
cancer
(BC)
is
a
prevalent
urinary
malignancy
and
muscle-invasive
bladder
(MIBC)
particularly
aggressive
associated
with
poor
prognosis.
One
of
MIBC
features
the
nuclear
atypia.
However,
molecular
mechanism
underlying
remains
unclear.
Here,
we
find
that
FKBP10
significantly
upregulated
in
tissues
correlated
metastasis
outcomes.
promotes
tumor
cell
invasion,
migration,
metastasis,
but
not
proliferation.
Notably,
enhances
atypia
BC
cells.
Mechanistically,
interacts
prelamin
A
hinder
entry
A,
thereby
leading
to
decrease
lamin
key
factor
involved
In
human
tissues,
downregulated
negatively
expression.
Overall,
our
findings
demonstrate
FKBP10/prelamin
A/lamin
axis
contributes
MIBC.
Journal of Cell Science,
Год журнала:
2025,
Номер
138(5)
Опубликована: Март 1, 2025
The
ability
of
cells
to
sense
and
respond
mechanical
signals
is
essential
for
many
biological
processes
that
form
the
basis
cell
identity,
tissue
development
maintenance.
This
process,
known
as
mechanotransduction,
involves
crucial
feedback
between
force
biochemical
signals,
including
epigenomic
modifications
establish
transcriptional
programs.
These
programs,
in
turn,
reinforce
properties
its
withstand
perturbation.
nucleus
has
long
been
hypothesized
play
a
key
role
mechanotransduction
due
direct
exposure
forces
transmitted
through
cytoskeleton,
receiving
cytoplasmic
central
function
gene
regulation.
However,
parsing
out
specific
contributions
from
those
surface
cytoplasm
remains
substantial
challenge.
In
this
Review,
we
examine
latest
evidence
on
how
regulates
both
via
nuclear
envelope
(NE)
epigenetic
machinery
elements
within
interior.
We
also
explore
establishing
memory,
characterized
by
mechanical,
transcriptomic
state
persists
after
stimuli
cease.
Finally,
discuss
current
challenges
field
present
technological
advances
are
poised
overcome
them.
International Journal of Molecular Sciences,
Год журнала:
2025,
Номер
26(5), С. 2125 - 2125
Опубликована: Фев. 27, 2025
Patients
with
chronic,
indolent
myeloproliferative
neoplasms
(MPNs)
are
at
risk
for
transformation
to
highly
lethal
leukemia,
although
targetable
mechanisms
driving
progression
remain
elusive.
We
discovered
that
the
High
Mobility
Group
A1
(HMGA1)
gene
is
up-regulated
MPN
in
patients
and
required
evolution
into
myelofibrosis
(MF)
or
acute
myeloid
leukemia
(AML)
preclinical
models.
HMGA1
encodes
epigenetic
regulators
modulate
chromatin
state
during
embryogenesis
tissue
regeneration.
While
silenced
most
differentiated
cells,
it
becomes
aberrantly
re-expressed
JAK2
mutant
(JAK2-V617F)
MPN,
highest
levels
after
secondary
MF
AML.
Here,
we
review
recent
work
highlighting
function
progression.
Though
underlying
continue
emerge,
increasing
evidence
suggests
functions
as
a
"chromatin
key"
"unlock"
regions
of
genome
involved
clonal
expansion
MPN.
Together,
these
findings
illuminate
driver
promising
therapeutic
target.
ABSTRACT
Viruses
and
bacteria
exploit
the
nuclear
pore
complex
(NPC)
host
functions
to
bypass
cellular
barriers
manipulate
essential
processes.
frequently
engage
directly
with
NPC
components,
such
as
nucleoporins,
enable
genome
import
evade
immune
defenses.
In
contrast,
bacterial
pathogens
rely
on
secreted
effector
proteins
disrupt
transport
reprogram
transcription.
These
strategies
reflect
a
remarkable
evolutionary
convergence,
both
types
of
targeting
promote
infection.
This
minireview
explores
overlapping
unique
mechanisms
by
which
hijack
nucleus,
shedding
light
their
roles
in
disease
potential
avenues
for
therapeutic
intervention.
Mutations
in
LMNA
cause
multiple
types
of
muscular
dystrophy
(
-MD).
The
symptoms
-MD
are
highly
variable
and
sensitive
to
genetic
background.
To
identify
contributions
this
phenotypic
variability,
we
performed
whole-genome
sequencing
on
four
siblings
possessing
the
same
mutation
with
differing
degrees
skeletal
muscle
disease
severity.
We
identified
a
variant
SMAD7
that
segregated
severe
disease.
functionally
test
variant,
generated
Drosophila
model
orthologous
fly
genes.
increased
SMAD
signaling
enhanced
defects
caused
by
mutant
lamin.
Conversely,
overexpression
wild-type
rescued
function.
These
findings
were
extended
humans
showing
is
biopsy
tissue
from
individuals
compared
age-matched
controls.
Collectively,
our
support
as
first
tested
modifier
for
suggest
components
pathway
therapeutic
targets.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Авг. 5, 2024
Abstract
In
the
cell
nucleus,
chromatin
is
anchored
to
nuclear
lamina,
a
network
of
lamin
filaments
and
binding
proteins
that
underly
inner
membrane.
The
lamina
involved
in
organisation
through
interaction
lamina-associated
domains
(LADs)
within
densely
packed
heterochromatin
regions.
Employing
cryo-focused
ion
beam
(cryo-FIB)
milling
conjunction
with
cryo-electron
tomography
(cryo-ET),
we
analysed
distribution
nucleosomes
at
lamin-chromatin
interface.
Depletion
A/C
reduced
concentration
periphery,
suggesting
lamins
are
directly
chromatin.
Using
microscopy
(cryo-EM),
then
identified
specific
motif
A
tail
domain
interacts
nucleosomes,
distinguishing
it
from
other
isoforms.
Furthermore,
examined
structure
dynamics
using
genome-wide
analysis
revealed
lamin-dependent
macroscopic-scale
alterations
gene
expression
remodelling.
Our
findings
provide
detailed
insights
into
dynamic
structural
interplay
between
isoforms
chromatin,
molecular
interactions
which
shaping
architecture
epigenetic
regulation.
D-β-hydroxybutyrate,
BHB,
has
been
previously
proposed
as
an
anti-senescent
agent
in
vitro
and
vivo
several
tissues
including
vascular
smooth
muscle.
Moreover,
BHB
derivatives
ketone
esters
alleviate
heart
failure.
Here,
we
provide
evidence
of
the
potential
therapeutic
effect
on
Hutchinson-Gilford
progeria
syndrome
(HGPS),
a
rare
condition
characterized
by
premature
aging
failure,
caused
presence
progerin,
aberrant
protein
derived
from
LMNA/C
gene
c.1824C
>
T
mutation.
We
have
assessed
hallmarks
HGPS-senescent
phenotype
vitro,
such
progerin
levels,
nuclear
morphometric
aberrations,
nucleolar
expansion,
cellular
senescent
morphology,
SA-βGal-positive
cells,
H3K9me3
heterochromatin,
γH2AX
foci,
Lamin
B1,
p21Waf1/Cip1
p16CDKN2A
abundance,
autophagy.
Strikingly,
improved
morphometrics,
diminished
senescence-phenotype,
unstuck
autophagy
HGPS
observed
enhanced
degradation
cargo
receptor
SQSTM1/p62,
suggesting
stimulation
autophagic
flux.
Additionally,
decrease
cause
senescence
HGPS.
Furthermore,
compound
C,
inhibitor
AMPK,
SBI-0206965,
ULK1/2
which
prevent
activation,
reversed
BHB-induced
decline
well
its
AMPK-mTORC1
dependent
manner.
Altogether,
these
results
suggest
that
anti-senescence
involves
clearance
activation
supporting
for
therapeutics
further
preclinical
trials.
Journal of Advanced Research,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 1, 2025
The
genetic
variants
of
LMNA
cause
an
array
diseases
that
often
affect
the
heart.
LMNA-related
cardiomyopathy
exhibits
high-penetrance
and
early-onset
phenotypes
lead
to
late-stage
heart
failure
or
lethal
arrhythmia.
As
a
subtype
dilated
arrhythmogenic
cardiomyopathy,
cardiac
dysfunction
is
resistant
existing
therapeutic
strategies,
leaving
major
unmet
clinical
need
in
management.
Here
we
comprehensively
summarize
current
knowledge
about
basis,
disease
models
pathological
mechanisms
cardiomyopathy.
Recent
translational
studies
were
highlighted
indicate
new
modalities
such
as
gene
supplementation,
silencing
genome
editing
therapy,
which
offer
potential
opportunities
overcome
difficulties
development
specific
drugs
for
this
disease.
involves
many
diverse
preclude
small-molecule
target
only
small
fraction
mechanisms.
Agreeing
notion,
first-in-human
trial
recently
reported
futility.
By
contrast,
therapy
offers
hope
directly
intervene
demonstrates
tremendous
breakthrough
Concepts
review
are
also
applicable
other
lack
effective
therapeutics.
