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Fundamentals of Cell Biology
Chapter 13: The Birth and Death of Cells
Dr. Saeb Aliwaini
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Cell cycle
– How cells make the decision to begin moving
through the stages of replication, and why some
cells never make this journey
– How cells decide to die
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Coordination of cell division
• A multicellular organism needs to coordinate cell
division across different tissues & organs
– critical for normal growth,
development & maintenance
• coordinate timing of
cell division
• coordinate rates of
cell division
• not all cells can have the
same cell cycle
Frequency of cell division
• Frequency of cell division varies by cell type
– embryo
• cell cycle < 20 minute
– skin cells
• divide frequently throughout life
• 12-24 hours cycle
– liver cells
• retain ability to divide, but keep it in reserve
M
metaphase anaphase
• divide once every year or two
telophase
prophase
C
G
– mature nerve cells & muscle cells
• do not divide at all after maturity
interphase (G , S, G phases)
mitosis (M)
cytokinesis (C)
G
• permanently in G0
S
2
1
2
1
New cells arise from parental cells that
complete the cell cycle
• Key Concepts :
– Cells divide by following carefully scripted program of molecular
events collectively called the cell cycle.
– The cell cycle is subdivided into five phases named G1, S, G2, M,
and G0. Cells not actively dividing reside in G1 or G0 phase.
– Progression through the cell cycle is under the control of proteins
that form checkpoints to monitor whether the proper sequence of
events is taking place. Cells halt at these checkpoints until they
complete the necessary steps to continue.
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Overview of Cell Cycle Control
• Two irreversible points in cell cycle
– replication of genetic material
– separation of sister chromatids
• Checkpoints
– process is assessed & possibly halted
sister chromatids
centromere
single-stranded
chromosomes

double-stranded
chromosomes

Checkpoint control system
• Checkpoints
– cell cycle controlled by STOP & GO chemical
signals at critical points
– signals indicate if key cellular
processes have been
completed correctly
Checkpoint control system
• 3 major checkpoints:
– G1/S
• can DNA synthesis begin?
– G2/M
• has DNA synthesis been completed
correctly?
• commitment to mitosis
– spindle checkpoint
• are all chromosomes attached to
spindle?
• can sister chromatids separate
correctly?
G1/S checkpoint
• G1/S checkpoint is most critical
– primary decision point
• “restriction point”
– if cell receives “GO” signal, it divides
• internal signals: cell growth (size), cell nutrition
• external signals: “growth factors”
– if cell does not receive
signal, it exits cycle &
switches to G0 phase
• non-dividing, working state
G0 phase
• G0 phase
– non-dividing, differentiated state
– most human cells in G0 phase
 liver cells
M
Mitosis
G2
Gap 2
S
Synthesis
 in G0, but can be “called
G1
Gap 1
G0
Resting
back” to cell cycle by
external cues
 nerve & muscle cells
 highly specialized
 arrested in G0 & can never
divide
Activation of cell division
• How do cells know when to divide?
– cell communication signals
• chemical signals in cytoplasm give cue
• signals usually mean proteins
– activators
– inhibitors
experimental evidence: Can you explain this?
“Point of no return”
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The G2/M checkpoint is the trigger for large-scale rearrangement
of cellular architecture
• MPF
Early experiments characterizing the activity of Mitosis
Promoting Factor.
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New cells arise from parental cells that
complete the cell cycle
– The G1/S checkpoint, called the restriction point or
start point, is where cells commit to completing cell
division.
– Proteins called cyclins play an important role in
advancing cells through checkpoints.
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Activation of cyclin-CDK complexes
begins in G1 phase
Figure 13.04: Scientists discovered the first cyclins when they noted that high cyclin levels
with the onset of mitosis in embryos. Cyclin levels drop sharply after this.
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Cyclins & Cdks
• Interaction of Cdk’s & different cyclins triggers the stages of
the cell cycle
“Go-ahead” signals
• Protein signals that promote cell growth &
division
– internal signals
• “promoting factors”
– external signals
• “growth factors”
• Primary mechanism of control
– phosphorylation
• kinase enzymes
• either activates or inactivates cell signals
Cell cycle signals
• Cell cycle controls
– cyclins
inactivated Cdk
• regulatory proteins
• levels cycle in the cell
– Cdk’s
• cyclin-dependent kinases
• phosphorylates cellular proteins
activated Cdk
– activates or inactivates proteins
– Cdk-cyclin complex
• triggers passage through different stages of cell
cycle
Control by cyclin/CDK complexes
Figure 13.05: Distinct cyclin-cdk complexes control progression through cell cycle
checkpoints.
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The cell cycle is divided into five
phases
• “Resting” cells reside
in G0 or G1 phase
• Several checkpoints
define critical
decision-making
events in the cell
cycle
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Figure 13.02: Checkpoints
control progression through the
cell cycle. Some of the major
checkpoints are shown.
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To start
• You need signals >>>>>
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Cell cycle step 1: Signal transduction initiates
cell cycle progression.
Figure 13.06: The family of
mitogen activated protein
kinases (MAPKs) and their
upstream regulatory proteins.
Figure 13.07: A simplified MAP
kinase signaling pathway.
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Cell cycle step 2: Changes in gene expression are required
for progression through the restriction point
• progression through the restriction point in mammalian
cells requires activation of at least two cyclin/CDK
complexes: cyclin D1/CDK4 (or CDK6) and cyclin
E/CDK2
• expression of most CDKs does not vary much
throughout the cycle, but without their corresponding
cyclins, they are not functional
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Cell cycle step 3: Pro- and anti-growth signaling
networks converge at the G1/S cyclin-CDK complexes
• Phosphorylation
• Binding by inhibitory
kinases
• Subcellular location
• Protein degradation
Figure 13.08: Summary of the
cyclin/cdk activation-inactivation cycle.
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• The key function of G1-Cdk complexes in animal cells is to activate
a group of gene regulatory factors called the E2F proteins, which
bind to specific DNA sequences in the promoters of a wide variety
of genes that encode proteins required for S-phase entry,
including G1/S-cyclins, S-cyclins, and proteins involved in DNA
synthesis and chromosome duplication.
• In the absence of mitogenic stimulation, E2F-dependent gene
expressionis inhibited by an inter- action between E2F and
members of the retinoblastoma protein (Rb) family.
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Cell cycle step 4: Active cyclin/CDKs phosphorylate
pocket proteins, which activate E2Fs
Figure 13.09: The transcription
factor E2F is inactivated by Rb
binding.
Figure 13.10: Examples of positive (green) and
negative (red) feedback loops controlling E2F
function.
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How E2Fs enhance expression of some genes
while suppressing expression of others remains
unclear
Figure 13.11: A model of how E2F transcription factors can suppress or activate gene
transcription.
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Cell cycle step 5: The DNA replication machinery is
activated by protein kinases
A key player is a large, multiprotein complex
called the origin recognition complex (oRc),
which binds to replication origins throughout
the cell cycle. In late mitosis and early G1, the
proteins cdc6 and other proteins bind to the
ORC at origins and help load a group of six
related proteins called the Mcm proteins. The resulting large complex is the pre-RC,
and the origin is now licensed
for replication.
Figure 13.12: Assembly of the prereplication complex.
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DNA replication occurs in S phase
• 3 key steps
Figure 13.13: Activation of
the replication complex.
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Cell cycle step 6: DNA integrity is ensured by the G1/S, S/G2,
and G2/M checkpoints
Figure 13.15: Growth arrest induced
by Chk1 and Chk2.
Figure 13.14: A current model for DNA repair.
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Cell cycle step 7: Cells increase in size
during G2 phase
Figure 13.17: Wee1 mutation affects cell size. Compared to normal ("wild-type," WT)
yeast, Wee1 mutants grow to half normal size before dividing.
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Cell cycle step 8: Cyclin B/CDK1 activation drives
cells through the G2/M checkpoint
Figure 13.18: A model for cell size control of
cell growth in yeast in G2.
Dr. Saeb Aliwaini
Figure 13.19: A model for how
adhesion to ECM promotes cell growth
in mammalian cells.
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Figure 13.20: Phosphorylation of Cdk1 primes it for activation but also keeps it in an
inactive state.
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Cell cycle step 9: Chromosome alignment is
ensured by the mitotic spindle assembly
checkpoint
Figure 13.21: A model for anaphase promotion by APC/C.
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Cell cycle step 10: Onset of cytokinesis is
timed to begin only after mitosis is complete
• Cytokinesis requires the contraction of the
contractile ring that lies just beneath the plasma
membrane, perpendicular to the long axis of the
mitotic spindle.
• It is important that the myosin motors in the ring
not activate until mitosis, including reconstitution
of the nuclear membrane, is complete.
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Multicellular organisms contain a cell selfdestruct program that keeps them healthy
• Key Concepts:
– Cells die either by traumatic injury (necrosis) or by a
self-destruct program called apoptosis.
– Apoptosis begins through at least two molecular
mechanisms, called intrinsic and extrinsic
pathways.
– The family of proteins called caspases includes
proteases that promote the degradation of
organelles and cytosolic proteins during apoptosis.
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Cells die in 2 different ways:
necrosis and apoptosis
Figure 13.22: Cellular damage can result in necrosis, as organelles swell and the plasma
membrane ruptures.
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Apoptosis is a property of all animal cells
and some plant cells
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Apotosis is voluntary
Figure 13.23: Sections of the interdigital web show cell death (dark-staining nuclei). This
cell death has the characteristics of apoptosis.
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Apoptosis is induced via at least
2 different pathways
Figure 13.24: Ligation of death receptors
causes the recruitment of the adaptor
protein FADD to the intracellular region of
the death receptor.
Figure 13.25: E2F1 lies at the heart of the
growth-versus-death decision making
system.
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Targets of pro- and anti-apoptotic
transcription factors are members
of bcl-2 family
Figure 13.26: The Bcl-2 family proteins
share up to four Bcl-2 homology domains
(BH) and can be antiapoptotic or
proapoptotic.
Figure 13.27: The Bcl-2 family of proteins
compete with members of the
antiapoptotoic group to access the
apoptotic group in an elaborate hierarchy.
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Mitochondrial Outer Membrane
Permeabilization (MOMP)
Figure 13.28: Signals for the induction of apoptosis trigger changes in the Bcl-2 family proteins, which function to
inhibit or promote apoptosis. Activation of caspase 9 by the apoptososme. Insert, three views of apoptosome
structure as determined by electron microscopy.
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Apoptosis triggers the activation of
special proteases: the caspases
Figure 13.29: Different types of vertebrate caspases are shown schematically.
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The final changes
• Stereotypical morphological changes take place
during apoptosis
– karyorrhexis
• Apoptotic cells are cleared by phagocytosis
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• The APC/C catalyzesthe ubiquitylation and destruction of two
major pro- teins. The first is securln,which normally protects
the protein linkages that hold sister chromatid pairs together in
early mitosis. Destruction of securin at the metaphase-toanaphasetransition activatesa proteasethat separatesthe
sisters and unleashes anaphase.The S- and M-cyclins are the
second major targets of the APC/c. Destroying these cyclins
inactivatesmost cdks in the cell
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