The
mammalian
CKS
family
consists
of
two
highly
conserved
proteins,
CKS1
and
CKS2.
Both
are
able
to
bind
to
cyclin
dependent
kinases
1
and
2
(CDK1
and
CDK2)
with
high
affinity
and
were
suggested
to
modulate
CDK
activity
and
thus
cell
cycle
control.
CKS
proteins
have
also
been
reported
to
facilitate
the
ubiquitination
of
cyclin
A
by
the
anaphase
promoting
complex
(APC).
Additionally
CKS1
has
been
shown
to
have
an
important
role
in
the
recognition
of
the
cyclin
dependent
kinase
inhibitor
p27Kip1
by
the
SCFSkp2
(Skp1-Cul1-F-box-protein)
ubiquitin
ligase.
Elevated
expression
of
both
CKS
proteins
is
often
found
in
a
variety
of
tumours
and
is
correlated
with
poor
prognosis.
This
might
indicate
an
involvement
of
CKS
proteins
in
the
process
of
transformation
from
normal
to
cancer
cells.
Previously
it
was
shown
that
down-regulation
of
CKS
proteins
in
cancer
derived
cell
lines
results
in
a
loss
of
their
high
proliferative
capacity.
I
surmise,
that
a
possible
oncogenic
effect
of
CKS
proteins
might
be
due
to
the
deregulation
of
replication.
To
study
the
role
of
CKS
proteins
as
oncogenes,
different
stages
of
cancer
development
were
modelled
in
the
human
diploid
fibroblast
cell
line,
IMR90.
Over-expression
of
CKS
proteins
was
combined
with
defined
genetic
events
known
to
be
associated
with
transformation
such
as
activation
of
telomerase
(hTERT)
and
blockage
of
the
p53
and
RB
pathways.
Over-expression
of
CKS
variants
in
IMR90
cells
led
to
checkpoint
activation
and
growth
arrest
reminiscent
of
oncogenic
stress.
Down-regulation
of
the
checkpoint
proteins
p53
and
RB
however
could
alleviate
the
growth
arrest
and
led
to
a
slight
growth
advantage
of
the
CKS
over-expressing
fibroblasts.
Analyses
to
understand
the
molecular
mechanisms
behind
the
checkpoint
activation
in
primary
IMR90
were
performed
addressing,
in
particular,
the
involvement
of
an
altered
CDK
activity.