BME 303/L5: The Cell Division Cycle
This lecture will cover:
• Overview of the cell cycle
• The cell-cycle control system
• G1 phase
• S phase
• M phase
• Mitosis
• Cytokinesis
• Control of cell numbers and cell size
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Quiz #1
Average = 2.41/3
High = 3.5
Low = 0.5
2
Homework #1
The paper “Discher et al., Science, 1999” has been
posted.
Assignment is due by Friday night 9/19 at midnight
Follow instructions in syllabus on how to write the
homework.
Please note that it is not acceptable to copy sentences
from journal articles, even if you use quotations!
DO NOT USE AI…there is now an AI feature in Turnitin
that checks for AI usage. If this shows >25% of report
was written by AI, that HW is a zero.
3
What is a Cell Cycle?
• Somatic cells duplicate
their contents and divide
• Eukaryotic
cells
divide every 8 to 20
hours.
• Prokaryotic cells like bacteria
divide every 45 minutes.
• Virus replicates 10.3 billion
copies/day.
Fig : 18-1, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
4
Cell Cycle is divided into 4 Phases
The eukaryotic cell cycle usually occurs in four phases.
Interphase: The cell grows continuously;
which consists of three phases: (G1, S, G2)
• Gap 1 – Cell grows
(the gap between M phase and S phase)
• S phase – DNA replication
• Gap 2 – Protein synthesis, Prepare for
cell division
(the gap between S phase and M phase)
M phase (mitotic phase):
•
Mitosis - Divide nucleus contents
(nuclear division)
•
Cytokinesis– Separation of a cell into
two cells
(cytoplasmic division)
Fig : 18-2, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
M phase is typically much shorter and G1 much longer than shown here.
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The G0 Phase
• G0 is a Quiescent or Resting State.
• Some cells like hepatocytes enter G0 temporarily.
• Differentiated cells like neurons spend their life in
G0.
6
Cell-Cycle Control System
The cell-cycle control system ensures that key processes in the cycle occur
in the proper sequence.
•
The cell-cycle control system
triggers Essential Processes
when it reaches Transition Points
•
Essential Processes:
-DNA Replication in S Phase
-The Segregation of duplicated
Chromosomes in Mitosis.
•
Extracellular or Intracellular
Conditions are unfavorable
-The cycle will be halt transiently at
specific transition points in G1, G2, or
M Phases
-Exp. DNA is damaged-unfavorable
Fig : 18-3, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
7
Cyclin-Dependent Protein Kinases (Cdks)
Cyclin-dependent kinase (Cdk) drives the progression of cell cycle.
•
Cyclins: Eukaryotic proteins involve in
controlling nuclear division via Cdk
activation
•
Cdk-inactive until bound to cyclin.
•
Dimerization of cyclin-Cdk
-autophosphorylation (signaling molecule)
-activates signaling pathways
•
Cell Cycle = Interphase + M phase
Fig : 18-2, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
Fig : 18-4, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
8
Distinct Cyclin and Cdk Complexes Controls Cell-Cycle
Fig : 18-8, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
Distinct Cdks associate with different cyclins to trigger the different events of
the cell cycle.
The accumulation of cyclins helps regulate the activity of Cdks.
• Active S cyclin and Cdks complex, called S-Cdk triggers S phase
• Active M cyclin and Cdks complex, called M-Cdk triggers M phase
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The Activity of Cdks Is Controlled By Various Mechanisms
1-The activity of some Cdks is regulated by cyclin degradation.
• Ubiquitylation of S or M
cyclin by APC/C
• Cyclin
destruction
proteasomes.
in
• The loss of cyclin = Cdk
inactive.
Fig : 18-9, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
2-The activity of a Cdk can be blocked by the binding of a Cdk inhibitor.
• The inhibitor protein (p27)
binds to an activated cyclin–
Cdk complex.
Fig : 18-11, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
• No Phosphorylation of
target proteins = no progress
through G1 into S phase.
3-The inhibitory phosphates must be removed (M-Cdk).
•Inhibitory protein kinase- Wee1
phosphorylates newly formed M
cyclin–Cdk complex - Inactive
•Phosphates are removed by an
activating protein phosphatase
called Cdc25 - Active
Fig : 18-10, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
10
Mechanisms to Pause The Cycle
The cell-cycle control system uses
various mechanisms to pause the
cycle at specific transition points.
The activity of Cdks could be;
-regulated
(APC/C)
by
cyclin
degradation
-blocked by the binding of a Cdk
inhibitor (p27)
-in inactive state until its phosphates
are removed by an activating protein
phosphatase (Cdc25)
Fig : 18-12, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
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Interphase – G1, S, G2 Cell Cycle
Interphase
Protein synthesis,
getting ready for
cell division
Active cell growth
Panel : 18-1 (Part 2), Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
•
Centrosome is duplicated
•
DNA is duplicated
•
Cell has doubled in size
•
M-cyclin levels are low
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The G1 Phase
• Cdks are stably inactivated in G1.
• Mitogens promote the production of the cyclins that
stimulate cell division.
• DNA damage can temporarily halt progression through G1.
• Cells can delay division for prolonged periods by entering
specialized nondividing states.
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Cell Proliferation
Fig : 18-14, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
•
Mitogens may stimulate cell proliferation is by inhibiting the Retinoblastoma (Rb)
protein.
•
NO mitogens- dephosphorylated Rb protein holds transcription regulators- inactive
state.
•
Mitogens+Receptors - the formation and activation of Cylin/Cdk complexes (G1-Cdk
and G1/S-Cdk complexes).
•
Those Cylin/Cdk complexes phosphorylate, and thereby inactive Rb protein- activate the
transcription of genes required for entry into S phase.
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DNA Damage can arrest the Cell Cycle in G1
DNA DAMAGE
Active Protein Kinases
Both active and stable the p53
protein (no degradation)
The transcription of the Cdk
inhibitor Protein p21.
The p21 protein binds to G1/SCdk and S-Cdk
Inactive Cyclin/Cdk complexes
Cell cycle arrests in G1.
Fig : 18-15, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
15
The S Phase
• S-Cdk initiates DNA replication and blocks rereplication. (more details in L19)
• Incomplete replication can arrest the cell cycle in G2.
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The M Phase
• The division of a cell into two daughters occurs in
the M Phase of the cell cycle.
• The M Phase consist of Mitosis (Nuclear Divison) and
Cytokinesis (Cytoplasmic Division) .
• M-Cdk drives entry into Mitosis.
• Cohesins and Condensins help configure duplicated
chromosomes for separation.
• Different cytoskeletal assemblies carry out Mitosis
and Cytokinesis.
• M phase occurs in stages.
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M-Cdk Creates a Positive Feedback Loop
Activated M-Cdk indirectly activates more M-Cdk, creating a positive feedback
loop.
Inactive Cdc25
Active Cdc25
Active M-Cdk
Phosphorylates
Cdk-activating
(Cdc25).
and activates
phosphatase
More Cdc25 = more active M-Cdk
by the removal of the inhibitory
phosphate groups
Fig : 18-17, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
18
Two Types of Cell Division
Mitosis:
- Cell division that occurs in somatic cells (cell body).
- Cell divides into two identical daughter cells
- Each daughter cell has same number of chromosomes as the parent cell
(diploid cell).
Meiosis:
- A specialized type of cell division that occurs
in sexual reproduction
involving germ cells.
- One cell divides into four daughter cells
- Each daughter cell has half the number of chromosomes of the parent
cell (haploid cell).
(It will be discussed in more detail in L23)
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Mitotic Cell Division
Panel : 18-1 (Part 1), Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
20
MITOSIS (Nuclear Division)
• Centrosomes duplicate to help form the two poles of the mitotic
spindle.
• The mitotic spindle starts to assemble in Prophase.
• Chromosomes attach to the mitotic spindle at Prometaphase.
• Chromosomes line up at the spindle equator at Metaphase.
• Chromosomes segregate during Anaphase.
• The nuclear envelope re-forms at Telophase.
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Review of Certain Terms
Centrioles
Adapted from Panel : 18-1 (Part 3), Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
•
Microtubules – form mitotic spindles
•
Centrosomes – where microtubules are organized – centrosome consists of
2 centrioles right-angle to each other
•
Chromosomes / chromatids – kinetochore divides the chromosome
into two chromatids
Cohesins and Condensins help to configure duplicated
chromosomes for segregation.
•
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Cohesins and Condensins
Fig : 18-18a, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
Cohesins tie together the two
adjacent sister chromatids in each
duplicated chromosome.
•
•
They form large protein rings that
surround the sister chromatids
They prevent sister chromatids
from coming apart, until the rings
are broken late in mitosis.
Fig : 18-18b, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
Condensins help coil each sister chromatid
(each DNA double helix) into a more compact
structure to be more easily segregated during
mitosis.
•
The exact mechanism how they might package
chromatids is not known.
23
Cytoskeletal Structures that Mediate M Phase
Fig : 18-19, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
Two transient cytoskeletal structures mediate M phase in animal cells.
•
The Mitotic spindle assembles first to separate the duplicated chromosomes. Then,
The Contractile ring assembles to divide the cell in two.
•
Whereas the Mitotic Spindle is based on Microtubules, the Contractile Ring is based
on Actin and Myosin.
•
Plant cells use a very different mechanism to divide the cytoplasm, as we discuss later.
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Sister Chromatids
Fig : 18-20, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
• Sister chromatids separate at the beginning of Anaphase.
• The mitotic spindle then pulls the separated sisters to opposite poles of the
cell.
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Centrosome
Fig : 18-21, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
•
The centrosome in an interphase cell duplicates to
form the two poles of a mitotic spindle.
•
Most animal cells contain a single centrosome, which
consists of a pair of centrioles (gray) embedded in a
matrix of proteins (light green).
•
Centrosome duplication begins at the start of S
phase and is complete by the end of G2.
•
Initially, the two centrosomes remain together, but, in
early M phase, they separate, and each nucleates its
own aster of microtubules.
•
The centrosomes then move apart, and the
microtubules that interact between the two asters
elongate preferentially to form a bipolar mitotic
spindle, with an aster at each pole.
•
When the nuclear envelope breaks down, the spindle
microtubules are able to interact with the duplicated
chromosomes.
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Mitotic Spindle
Fig : 18-22, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
•
A bipolar mitotic spindle is formed by the
selective
stabilization
of
interacting
microtubules.
•
New microtubules grow out in
directions from the two centrosomes.
•
The two ends of a microtubule (the plus and
the minus ends) have different properties, and it
is the minus end that is anchored in the
centrosome.
•
The free plus ends are dynamically unstable and
switch suddenly from uniform growth (outwardpointing red arrows) to rapid shrinkage (inwardpointing blue arrows).
•
When two microtubules from opposite
centrosomes interact in an overlap zone, motor
proteins and other microtubule-associated
proteins cross-link the microtubules together
(black dots).
•
This stabilizes the plus ends by decreasing the
probability of their depolymerization.
random
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Kinetochores
Fig : 18-23, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
Kinetochores attach chromosomes to the mitotic spindle.
(A) A fluorescence micrograph of a duplicated mitotic chromosome. The kinetochores are
stained red with fluorescent antibodies that recognize kinetochore proteins.
(B) Schematic drawing of a mitotic chromosome showing its two sister chromatids
attached to kinetochore microtubules, which bind to the kinetochore at their plus ends.
Each kinetochore forms a plaque on the surface of the centromere.
(C) Each microtubule is attached to the kinetochore via interactions with multiple copies of
an elongated connecting protein complex (blue).
•
These complexes bind to the sides of the microtubule near its plus end, allowing the
microtubule to grow or shrink while remaining attached to the kinetochore.
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Three Types of Microtubules
Fig : 18-24, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
Three types of Spindle Microtubules make up the Mitotic Spindle.
(A) Three types of spindle microtubules are: Astral Microtubules, Kinetochore
Microtubules, and Interpolar microtubules. In reality, the chromosomes are much
larger than shown, and usually multiple microtubules are attached to each
kinetochore.
(B) Fluorescence micrograph of duplicated chromosomes aligned at the center of the
mitotic spindle. In this image, kinetochores are red dots, microtubules are green, and
chromosomes are blue.
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Mitotic Phase – Prophase
Total chromosomes = 46
Adapted from Panel : 18-1 (Part 3), Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
•
Microtubules reorganize to make astrals (spindles)
•
Centrosomes move to opposite poles
•
Chromosomes condense
•
Kinetochore is formed on chromosome strand to generate two sister chromatids
•
Nuclear envelope begin to break
The nuclear envelope breaks down and re-forms during mitosis.
30
M Phase – Prometaphase
Adapted from Panel : 18-1 (Part 4), Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
•
Chromosomes are attached to spindles at the kinetochore.
•
Chromosomes undergo oscillation movement back and forth on the spindle.
• Chromatids attached at the kinetochores are pulled away to two opposite
poles by
the pair of centrioles.
•
M-cyclin levels are high.
31
M Phase – Metaphase
Adapted from Panel : 18-1 (Part 5), Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
•
Chromosomes are aligned at the equator of the spindle, midway between the
spindle poles.
•
Paired kinetochore microtubules on each sister chromatid are attached to
opposite poles of the spindle
•
Mitotic checkpoint ensures the fidelity of this bi-polar attachment.
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M Phase – Anaphase
Adapted from Panel : 18-1 (Part 6), Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
•
M-cyclin is at the lowest level
•
Paired chromatids are separated from spindle equator and pulled towards the opposite
poles at the kinetochore by the centrioles.
•
Kinetochore microtubules shorten and the sister chromatids are pulled toward opposite
poles- Anaphase A movement
•
The two spindle poles move apart by (1) the Elongation of spindles (2) forces
exerted on astral microtubules at each spindle pole pull the poles away from each
other Anaphase B movement
•
Plant cells generally do not have centrosomes and therefore have less sharply defined
spindle poles than do animal cells;
33
M Phase – Telophase
Adapted from Panel : 18-1 (Part 7), Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
•
Two sets of chromosomes are formed at the spindle pole
decondense.
•
Nuclear envelope begins to reform.
•
Cleavage furrow (Contractile Ring) begins to form at the middle of 2 daughter
cells on the circumference of the cell.
and begin to
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M Phase – Cytokinesis
Total
chromosomes
= 46
Two identical
daughter cells
Total
chromosomes
= 46
Adapted from Panel : 18-1 (Part 8), Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
•
Division of the cytoplasm is completed by the Contractile Ring of actin and myosin
filaments at the cleavage furrow.
•
Produces two identical Diploid daughter cells (2n).
•
Cells re-enter interphase in G1.
•
Microtubules reform their interphase organization.
35
Central Spindle
The mechanism is still uncertain.
Fig : 18-32, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
•
In
Anaphase
overlapping
Interpolar
Microtubules
form
Central Spindle.
•
The Central Spindle then recruit
and activate proteins that signal
the cell cortex to assemble the
Contractile Ring.
•
Position of the Cleavage Furrow is
dictated by the Central Spindle.
•
In this model, the Interpolar
Microtubules recruit proteins that
generate a signal (red arrows) that
activates a protein called RhoA in
the cell cortex.
•
RhoA, a member of the Rho family
of GTPases, controls the assembly
and contraction of the Contractile
Ring
midway
between
the
Spindle Poles.
•
The two daughter cells will be
equal size.
36
Contractile Ring
Fig : 18-33a, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
• The Contractile Ring divides the cell in two.
• Schematic diagram of the mid region of a dividing cell showing the Contractile
Ring beneath the plasma membrane and the remains of the Interpolar
Microtubules.
37
Cytokinesis in Plants
Fig : 18-35, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
Cytokinesis in a plant cell is guided by a specialized microtubule-based structure called
the Phragmoplast.
(A) At the beginning of Telophase, after the chromosomes have segregated, a new cell wall
starts to assemble inside the cell at the equator of the old spindle.
(B) The Interpolar Microtubules of the mitotic spindle remaining at Telophase form the
phragmoplast and guide The vesicles, which are filled with cell wall material, derived from
the Golgi apparatus, toward the equator of the spindle. They fuse to form the growing new cell
wall that grows outward to reach the plasma membrane and original cell wall.
(C) The preexisting plasma membrane and the new membrane surrounding the new cell wall
then fuse, completely separating the two daughter cells.
(D) A light micrograph of a plant cell in telophase is shown at a stage corresponding to (A). The
location of the growing new cell wall is indicated by the arrowheads.
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Apoptosis
Apoptosis is mediated by an intracellular Proteolytic Cascade.
Survival Factors suppress apoptosis by regulating Bcl2 family members.
Fig : 18-39, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
Inactive Procaspase
Apoptotic Signal
Active Initiator Caspases
Active Executioner Caspases
Cleave key proteins
Apoptosis
Fig : 18-42, Essential Cell Biology, Fifth Edition
Copyright © 2019 W. W. Norton & Company
Cell-surface Receptors
The Survival Factor
Active Intracellular Signaling Pathway
Activate Transcription Regulator
Activates Bcl2 gene
NO Apoptosis
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