REGULATION OF CELL CYCLE
SALMAN UL ISLAM, (MS),
CELLULAR BIOCHEMISTRY LAB.
Overview of the cell cycle
Cell-cycle control system
“Where a cell arises, there must be a previous cell,
just as animals can only arise from animals and
plants from plants.
A cell reproduces by carrying out an orderly
sequence of events in which it duplicates its
contents and then divides in two.
This cycle of duplication and division, known as the
cell cycle, is the essential mechanism by which all
living things reproduce.
How is cell division and
-- stimulate cell growth
-- trigger cell division
-- disable apoptotic mechanisms
Cell Cycle Regulation
OVERVIEW OF THE CELL CYCLE
The eucaryotic cell cycle is traditionally divided into
M phase: constituted by mitosis (nucleus division)
and cytokinesis (cell splits in two). The period
between one M phase and the next is called
interphase. The interphase encompasses the
remaining three phases of the cell cycle.
S phase ( S=synthesis): the cell replicates its
nuclear DNA. S phase is flanked by two phases in
which the cell continues to grow.
G 1 phase (G= gap): it is the interval between the
completion of M phase and the beginning of S
phase (DNA synthesis).
G2 phase: interval between the end of S phase and
the beginning of M phase.
CHECKPOINTS IN CELL-CYCLE REGULATION
Two important checkpoints occur in G1 and G2.
The G1 checkpoint allows the cell to confirm that
the environment is favorable for cell proliferation
and its DNA is intact before committing to S phase.
G2 checkpoint ensures that cells do not enter
mitosis until damaged DNA is repaired and DNA
replication is complete.
CELL-CYCLE CONTROL SYSTEM
DEPENDS ON CYCLICALLY ACTIVATED
Key proteins are activated and then inactivated that
regulate DNA replication, mitosis, and cytokinesis.
Phosphorylation followed by dephosphorylation is
one of the most common ways to switch the activity
of proteins on and then off.
Protein kinases are activated at appropriate times
in the cycle, after which they quickly become
Switching these kinases on and off is done by
cyclins, so kinases are therefore known as cyclindependent protein kinases or Cdks.
CDKS ACTIVITY IS ALSO REGULATED BY
PHOSPHORYLATION AND DEPHOSPHORYLATION
For M-Cdk to be maximally active, it has to
phosphorylated at one or more sites by a specific
protein kinase, and dephophorylated at other sites
by specific protein phosphatase.
The removal of the inhibitory phosphate groups by
the phosphatase is the final step that activates the
M-Cdk at the end of interphase.
Then M-Cdk complex can activate more of the
same complexes. This positive feedback produces
the sudden, explosive increase in M-Cdk activity
that drives the cell abruptly into M phase.
CDKS ARE REGULATED BY ACCUMULATION AND
DESTRUCTION OF CYCLINS
Cyclin concentration plays an important part in
timing the events of cell cycle.
M cyclin= cyclin that helps drive cells into M phase.
M-cyclin synthesis starts immediately after cell
division and continues steadily throughout
interphase. The cyclin concentrates, so that its
concentration rises gradually and helps time the
onset of mitosis; its rapid elimination then helps
initiate the exit from mitosis.
CDKS ARE REGULATED BY ACCUMULATION
AND DESTRUCTION OF CYCLINS (CONT…)
As mitosis nears completion, multiple molecules of
the protein ubiquitin are covalently attached to the
M-cyclin by anaphase promoting complex (APC).
This ubiquitination marks the cyclin for degradation
in proteosomes, large proteolytic machines found in
all eucaryotic cells. Destruction of the cyclin
inactivates the Cdk.
Distinct Cdks associate with
different cyclins to trigger the
different events of the cell
S-PHASE CYCLIN-CDK COMPLEXES
INITIATE DNA REPLICATION ONCE PER
Initiates DNA replication and helps block Rereplication.
DNA replication begins at origins of replication.
Origin recognition complex (ORC) remains bound to the
origin of replication; serves as a sort of landing for other
Cdc6 binds to ORC in G1, promotes additional proteins
binding to form pre-replicative complex, making the
replication origin ready to “fire”. S-Cdk then pulls the
“trigger” initiating DNA replication.
S-Cdk helps phophorylate Cdc6, causing it and the
other proteins in the pre-replicative complex to
dissociate from the ORC after an origin has fired.
CELL CYCLE ARREST
The cell-cycle control system can arrest the cycle at
specific checkpoints. The molecular mechanisms of
these are poorly understood.
In some cases, however, Cdk inhibitor proteins
come into play.
For example DNA damage causes increased
concentration and activity of p53 (gene regulatory
protein) which activates the transcription of a gene
encoding a Cdk inhibitor protein called p21.
The p21 protein binds to G1/S-Cdk, preventing
them from driving the cell into S phase.
CELLS CAN DISMANTLE THEIR CONTROL SYSTEM
AND WITHDRAW FROM THE CELL CYCLE
This is a different matter from pausing in the middle
of a cycle.
In human body, e.g, nerve cells and skeletal muscle
cells persist for a lifetime without dividing, they
G0 is modified G1 state in which the cell-cycle
control system is largely dismantled, in that many of
the Cdks and cyclins disappear.
The G1 checkpoint is therefore sometimes called
Start, passing it represents a commitment to
complete a full dividion cycle.
• Cell type
• Early frog embryo cells
• Yeast cells
• Intestinal epithelial cells
• cultured fibroblasts
• Human liver cells
Cell cycle time
The control system depends on a set of proteins
kinases, each composed of Cyclin and Cdk.
The control system also depends on protein complexes
such as APC.
The Cdks are cyclically activated by both cyclin binding
and the phosphorylation of some amino acids and the
dephosphorylation of others; when activated, Cdks
phophorylate key proteins in the cell.
The cell cycle control system can halt the cycle at
specific check points to ensure that the next step in the
cycle does not begin before the previous one has
finished, and intracellular and extracellular conditions