Cell Cycle Control and Cell Division Flashcards
The cell-cycle involves DNA replication and dividing the cell to
create
two identical daughter cells
The cell-cycle control system triggers the major events of the
cell cycle
As the cell cycle proceeds a series of (2) ensure
that each phase is complete before the next one begins
transitions or checkpoints
There are - major checkpoints in eukaryotic cells
3
The cell-cycle control machinery therefore controls
cell proliferation
— is essentially inappropriate proliferation
Cancer
Many of the genes (proteins) involved in cell-cycle regulation are
critical determinants of
cancer progression
The system depends on cyclically activated
cyclin-dependent protein kinases (Cdks)
The cell-cycle control system depends on
cyclical proteolytic events
The cell-cycle control depends on
transcriptional regulation
The Cell-Cycle Control System triggers the events that occur in each phase of
the
cell cycle
The Cell-Cycle Control System ensures the proper (3)
timing, order and fidelity of
the events
The Cell-Cycle Control System responds to (2)
intracellular and extracellular signals
The Cell-Cycle Control System arrests the cycle whenever the cell (2)
fails to
complete an essential cell-cycle process or
encounters unfavorable intracellular or
extracellular conditions
Control of the Cell-cycle by (2)
Cyclins and Cyclin-Dependent Protein Kinases (Cdks)
Cyclin-dependent kinase (Cdk) requires the binding of — and subsequent specific — to become an active enzyme
cyclin
phosphorylation
In the absence of cyclin, Cdk is in an — state
inactive
The concentrations of the three major cyclin proteins
— during the cell cycle
oscillate
their expression is —
to promote transitions through the cell cycle
induced
The concentrations of the Cdk…
do not change
constitutive expression
concentration do not change
The appearance and disappearance of the various cyclins
are critical for determining the
transitions from one phase
of the cell-cycle to the next
in addition, the Anaphase-Promoting Complex or
Cyclosome (APC/C) initiates the
metaphase to anaphase
transition
G1-Cdk cyclin
D
G1/S-Cdk cyclin
E
S-Cdk cyclin
A
M-Cdk cyclin
B
In the inactive state the catalytic or active site of the cyclin-dependent
kinase is blocked by the presence of a region called the
T-loop
Binding
of the specific cyclin to its cognate cyclin-dependent kinase leads to
a
movement of the T-loop away from the active site, leading to partial
activation
Cdk-activating kinase (CAK) can then
phosphorylate the T-
loop at a threonine residue in the T-loop resulting in full activation of
the cyclin-Cdk
Each cyclin partner is important for
determining which specific targets are
subsequently phosphorylated by the Cdk
subunit
Each cyclin-Cdk can induce different effects at
different times in the cell-cycle based upon the (3)
relative presence, absence or abundance of
each specific target, which can change
depending upon the phase of the cell cycle
Activation of the — — is
prerequisite for downstream events, however
the activity of each complex is finely regulated
by additional mechanisms
Cyclin-Cdk complex
Just as mutations that alter cyclin or Cdk
function can lead to misregulation of the cell
cycle, so too can mutations that
disrupt any of
these regulatory mechanisms create the
possibility that a cancer of some type may occur
The activity of cyclin-Cdk is further regulated by
Wee1 kinase
Cdc25
Wee1 kinase
further phosphorylates Cdk and renders it inactive
Cdc25 phosphatase
dephosphorylates and restores activity
APC/C is a member of the — — family of proteins
ubiquitin ligase
APC/C catalyzes the (2)
ubiquitylation and degradation of securin and the S- and M-cyclins
— is involved in protecting the protein linkages that hold the sister chromatids
together
Securin
Securin degradation leads to
activation of a protease that then separates
the sisters and unleashes anaphase
Degradation of the S- and M-cyclins leads to inactivation of the
Cdks
loss of the
Cdks means that their targets can be
dephosphorylated by various phosphatases
that are present in anaphase, which completes M phase
APC/C is activated in
mid-mitosis and remains active in G1
APC/C is activated in mid-mitosis and remains active in G1, which provides a period
in which Cdk is —
inactive
When the G1/S-Cdks are activated in late G1, — is
turned off
APC/C
This allows for — accumulation to start the next cell-cycle
cyclin
APC/C activity changes during the cell cycle due to its interactions with — in
anaphase and — from late mitosis through early G1
Cdc20
Cdh1
Control of the Cell-Cycle by —
Proteolysis
SCF
Ubiquitin ligase like APC/C
SCF contains - subunits
3
S, C and F
SCF
Ubiquitylates Cdk inhibitor (CKI) proteins in
late G1 such as p27
Ubiquitylation of proteins is a key step in the
initiation of many proteins “marked” for
degradation by the proteasome complex
— is a CKI family member that binds to the active cyclin-Cdk complex
p27
p27 binds to both the
cyclin and the Cdk subunits
This distorts the active
site of the — and p27 also inserts into the ATP-binding site, further
Cdk
inhibiting the enzyme activity
SCF associates with an — protein that is required for
F-box
binding to specific
protein targets
2 additional proteins (2) assist in the addition of multiple
ubiquitin molecules to the CKI and this targets the protein for degradation in the
proteosome complex
E1 and E2
Cyclin gene expression is regulated and
specific cyclins genes are induced (turned on)
as
the cell cycle transitions from one phase to
the next
Many other key regulatory proteins are
regulated at the — level
transcriptional
CAK
phosphorylates an activating site in Cdks
Wee1 kinase
phosphorylates inhibitory sites in cdks; primarily involved in suppressing cdk1 activity before mitosis
cdc25 phosphatase
removes inhibitory phosphates from cdks
p27
suppresses G1/S-cdk and s-cdk activities in G1
p21
suppresses G1-S-cdk and S-cdk activities following DNA damage
p16
suppresses G1-cdk activity in G1
APC/C
catalyzes ubiquitination of regulatory proteins involved primarily in exit from mitosis, including securing and S and M cyclins; regulated by association with activating subunits
cdc20
APCC activating subunit in all cells; triggers initial activation of APCC at metaphase to anaphase transition; stimulated by M-cdk activity
cdh1
APCC activating subunit that maintains APCC activity after anaphase and throughout G1; inhibited by Cdk activity
SCF
catalyzes ubiquitylation of regulatory proteins involved in G1 control, including some CKIs
Cell-Cycle Control
The central component of the control system is the
series of cyclin-Cdk complexes that regulate
transitions through the various phases
The complexes are also regulated by various inhibitory mechanisms, which provide information about the (3)
extracellular environment, DNA or cell
damage and whether each step in the cell-cycle has been properly completed
G0 represents a
resting or quiescent state
Cells can remain in G0 for
days to weeks or
longer before resuming proliferation
Cells can enter G0…
permanently until the cell
dies
Cells enter G0 from a cell-cycle checkpoint in the
G1 phase
G0 generally occurs due to (2)
lack of growth factors or nutrients
When does G0 occur in cells?
when they reach maturity
wells become terminally differentiated, such as nerve cells, heart muscle cells, or bone osteocytes
The — complex
binds exclusively to
deacteylated histone
H4
dREAM
what causes cells to move into G0?
dREAM complex
— associated co-activators promote transcription
E2F
co-repressors of either
E2F and pRB lead to histone modifications that result in (2)
histone compaction and
suppression of gene expression
