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Sphingosine kinase-2 maintains viral latency and survival for KSHV-infected endothelial cells.
[primary effusion lymphoma]
Phosphorylation
of
sphingosine
by
sphingosine
kinases
(
SphK
1
and
SphK
2
)
generates
sphingosine-
1
-
phosphate
(
S
1
P
)
,
a
bioactive
sphingolipid
which
promotes
cancer
cell
survival
and
tumor
progression
in
vivo
.
We
have
recently
reported
that
targeting
SphK
2
induces
apoptosis
for
human
primary
effusion
lymphoma
(
PEL
)
cell
lines
infected
by
the
Kaposi
's
sarcoma
-associated
herpesvirus
(
KSHV
)
,
and
this
occurs
in
part
through
inhibition
of
canonical
NF-κB
activation
.
In
contrast
,
pharmacologic
inhibition
of
SphK
2
has
minimal
impact
for
uninfected
B-
cell
lines
or
circulating
human
B
cells
from
healthy
donors
.
Therefore
,
we
designed
additional
studies
employing
primary
human
endothelial
cells
to
explore
mechanisms
responsible
for
the
selective
death
observed
for
KSHV-infected
cells
during
SphK
2
targeting
.
Using
RNA
interference
and
a
clinically
relevant
pharmacologic
approach
,
we
have
found
that
targeting
SphK
2
induces
apoptosis
selectively
for
KSHV-infected
endothelial
cells
through
induction
of
viral
lytic
gene
expression
.
Moreover
,
this
effect
occurs
through
repression
of
KSHV-microRNAs
regulating
viral
latency
and
signal
transduction
,
including
miR-K
12
-
1
which
targets
IκB
α
to
facilitate
activation
of
NF-κB
,
and
ectopic
expression
of
miR-K
12
-
1
restores
NF-κB
activation
and
viability
for
KSHV-infected
endothelial
cells
during
SphK
2
inhibition
.
These
data
illuminate
a
novel
survival
mechanism
and
potential
therapeutic
target
for
KSHV-infected
endothelial
cells
:
SphK
2
-
associated
maintenance
of
viral
latency
.
Diseases
Validation
Diseases presenting
"associated maintenance of viral latency"
symptom
primary effusion lymphoma
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