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The most important occurrence within the life of a cell are its
generation from a progenitor followed by its demise, either
through a natural or through a pathological process.
Regulation of both processes is critical to ensure that the
appropriate number of cells is available to carry out their
function within the organism.
Safeguard are also needed to protect against uncontrolled
growth, which may result in malignancy and the death of
organism in which the cell is a participant.
The Cell Cycle
Dr. Ahmad Salahuddin
When an organism requires additional cells, either for
growth or to replace those normally lost, new ones must
be produced by cell division, or proliferation.
Cellular turnover is a normal function.
The turnover times for some cells in the adult body are
slow or nonexistent (in the endocrine and central
nervous system, for example),
whereas other cells turnover very rapidly.
Somatic cells are generated by the division of existing
cells in an orderly sequence of events.
For a cell to generate two daughter cells, complete
copies of all of the cell’s constituents must be made and
shared between the two newly formed daughter cells.
This sequence of duplication is known as the cell cycle
and is the essential mechanism of eukaryotic
reproduction.
The cell cycle may be broadly divided into three
distinct stages: interphase, mitosis, and cytokinesis.
Interphase is the period between successive rounds of
nuclear division and is distinguished by cellular growth
and new synthesis of DNA.
It can be further subdivided into three phases called G1
phase, S phase, and G2 phase.
Division of genetic information occurs during the
stage of the cell cycle known as mitosis.
Mitosis can be divided into five distinct phases
called prophase, prometaphase, metaphase,
anaphase, and Telophase.
Mitosis assures that each daughter cell will have
identical complete functional copies of the parent
cell’s genetic material.
The third stage, cytoplasmic division or
cytokinesis, culminates with the separation into
two distinct daughter cells that enter
interphase.
INTERPHASE
All cells, whether actively cycling or not, spend the
vast majority of their lives in interphase.
Interphase is an eventful and important part of the
cell cycle and comprises G1, S, and G2 phases.
Cellular growth and DNA synthesis occur during
interphase, resulting in a duplication of cellular
materials so that there are sufficient materials for two
complete new daughter cells.
G1 and G0 phases
G1 phase is generally both a growth phase and a
preparation time for DNA synthesis of S phase.
During G1 phase: organelles and intracellular structures
are duplicated, RNA and protein are synthesized and the
cell grows.
Those cells in G1 phase that are not committed to DNA
synthesis are in a specialized resting state called G0
phase.
The restriction point is located within G1 phase and, if
passed, will commit a cell to continuing into S phase.
The restriction point is critical for cell cycle regulation.
The length of G1 phase is the most variable among cell
types.
Very rapidly dividing cells, such as growing embryonic
cells, spend very little time in G1 phase.
On the other hand, mature cells that are no longer
actively cycling are permanently in G1 phase.
S phase
Synthesis of nuclear DNA, also known as DNA
replication, occurs during S phase.
Each of the 46 chromosomes in a human cell is
copied to form a sister chromatid.
Actively cycling cells spend approximately 6 h in S
phase.
G2 phase
G2 is a safety gap allows the cell to ensure that DNA
synthesis is complete before proceeding to nuclear
division in mitosis.
Also contained with the G2 is a checkpoint where
intracellular regulatory molecules assess nuclear
integrity.
Typically, this phase lasts for approximately 4 h.
MITOSIS
Mitosis or nuclear division is a continuous process
divided into five phases based on progress made to a
specific point in the overall nuclear division.
Dividing cells spend about 1 h in mitosis.
After completion of nuclear division, cytokinesis
occurs.
Prophase
In prophase, the nuclear envelope remains intact and The
nucleolus disassembles.
Chromosomes of mitotic cells contain two chromatids
connected to each other at a centromere.
Specialized protein complexes, called kinetochores, form
and associate with each chromatid.
Mitotic spindle microtubules will attach to each
kinetochore.
The microtubules of the cytoplasm disassemble and
then reorganize on the surface of the nucleus to form
the mitotic spindle.
Two centriole pairs push away from each other by
growing bundles of microtubules forming the mitotic
spindle.
Prometaphase
The disassembly of the nuclear envelope marks the
beginning of pro-metaphase.
Spindle microtubules bind to kinetochores and
chromosomes are pulled by the microtubules of the
spindle.
Metaphase
Metaphase is characterized by chromatids aligned
at the equator of the spindle, halfway between the
two poles.
The aligned chromatids form the metaphase plate.
Anaphase
The mitotic poles are pushed further apart as a result of
polar microtubules elongating.
Each centromere splits in two and paired kinetochores
also separate.
Sister chromatids migrate toward the opposite poles of
the spindle.
Telophase
Telophase is characterized by kinetochore microtubule
disassembly and mitotic spindle dissociation.
Nuclear envelopes form around each of the two nuclei
containing the chromatids.
The chromatids decondense into dispersed chromatin
and nucleoli reform in the daughter nuclei.
CYTOKINESIS - COMPLETION OF A
CELL CYCLE
In order to create two distinct, separate daughter cells,
cytoplasmic division follows nuclear division.
An actin microfilament ring forms.
Contraction of this actin-based structure results in the
formation of a cleavage furrow that is seen beginning
in anaphase.
The furrow deepens until opposing edges meet.
Plasma membranes fuse on each side of the deep
cleavage furrow and the result is the formation of
two separate daughter cells, each identical to the
other and to the original parent cell.
CELL CYCLE REGULATORS
Cell cycle regulators control cell cycle progression.
Cell cycle mediators are categorized as cyclins or as cyclindependent kinases (CDKs).
Complexes of cyclins with CDKs (cyclin-CDKs complexes)
possess enzymatic activity.
Cyclin-dependent kinase inhibitors (CKI) can inhibit cyclin-CDKs
complexes.
Cyclins
The cyclins, categorized as cyclins D, E, A, or B, are a
family of cell cycle regulatory proteins that regulate
specific phases of the cell cycle.
Cyclins D are G1 regulators critical for progression
through the restriction point.
S phase cyclins include cyclins E and A.
Mitotic cyclins include cyclins B and A.
Cyclin-dependent kinases
Certain cyclins form complexes with certain CDKs to
stimulate the kinase activity of the CDKs.
Cyclin
Kinase
Function
D
CDK4
CDK6
Progression past the restriction
point at the G1/S boundary.
E
A
CDK2
B
CDK1
Transition from G1 to S.
Initiation of DNA synthesis in early S
phase.
Transition from G2 to M.
Initiation of mitosis.
CHECKPOINT REGULATION
Checkpoints placed at critical points in the cell cycle
monitor the completion of critical events and, if
necessary, delay the progression to the next stage of
the cell cycle.
One such checkpoint is the restriction point in G1 and
G2.
Tumor suppressors and checkpoints
Tumor suppressor proteins normally function to halt the
cell cycle progression within G1 when the cell should not
continue past the restriction point.
Mutated tumor suppressor genes may encode proteins that
permit cell cycle progression at inappropriate times.
Cancer cells often show mutations of tumor suppressor
genes.
G1 checkpoint:
It is important that nuclear synthesis of DNA not begin
until all the appropriate cellular growth has occurred during
G1.
Therefore, there are key regulators that ensure that G1 is
completed prior to the start of S phase (eg: RB and p53).
Retinoblastoma (RB) protein:
This tumor suppressor functions to halt a cell in the
resting or G1 phase of the cell cycle.
The RB gene is mutated in an inherited eye
malignancy known as hereditary RB.
p53:
Nuclear DNA damage results in activation of p53.
Activated p53 stimulates CKI transcription to produce a
protein named p21, to halt cell cycle progression to allow for
DNA repair.
If the damage is irreparable, p53 triggers apoptosis.
Unregulated cell cycle progression can occur in the presence
of mutated p53 because it is incapable of arrest the cell cycle.
Over 50% of all human cancers show p53 mutations.
G2 checkpoint
It is important for the integrity of the genome and of the cell
that nuclear division (mitosis) does not begin before DNA is
completely duplicated during S phase.
Therefore, the G2 checkpoint, which occurs after S and
before the initiation of mitosis, is also a critical regulatory
point within the cell cycle.
CDK1 controls the transition from G2 to M.