Ch.

18: Cell Cycle Control and Cell Death

I. Overview of the Cell Cycle

A. Definition
1. cells duplicate their contents and divide into 2 identical daughter cells
2. cell cycle regulation
a. coordinating cell cycle
b. regulating proliferation
B. Four Phases
1. G1 phase: gap b/n M and S
a. G=gap
b. cell monitors external and internal environments ensuring conditions
are suitable for start of S phase
2. S phase: DNA replication
a. S=synthesis
3 G2 phase: gap b/n S and M

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a. cell decides whether to proceed to mitosis or allow more time to

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prepare

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4. M phase: nucleus and cytoplasm divide

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a. mitosis: nucleus divides; cytokinesis: cytoplasm divides

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b. chromosome condensation marks the start of M phase
rs e i. makes chromosomes easier to segregate
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5. interphase (G1-S-G2) is the period b/n one M phase and the next
a. cell transcribes genes, synthesizes protein, and grows in mass
b. G1 and G2 allow the time for cell to double its mass before division
o

C. Central Control System Triggers the Major Processes of the Cell Cycle
aC s

1. how do cell coordinate all the machinery required for duplication and division?
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a. cell-cycle control system

i. ensures correct progression through the cell cycle by regulating
the cell-cycle machinery
2. cell-cycle control system is a complex network of regulatory proteins
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a. core: series of biochemical switches

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3. events of the cell cycle must occur in a particular sequence

a.. central control system triggers essential processes
b. regulated by feedback from the processes being performed
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4. control system stops cycle at various checkpoints

a. next step isn’t triggered unless cell is prepared
Th

b. G1 checkpoint: makes sure DNA is intact before entering S phase

i. G0: resting state used when extracellular conditions are
unfavorable for proliferation
some cells are always in G0: not dividing
sh

-called G1 arrest cells

-nerve and skeletal muscle cells
c. G2 checkpoint: ensures cell don’t enter mitosis until damaged DNA is
repaired and DNA replication is complete
II. The Cell-Cycle Control System
A. Depends on Cyclically Activated Protein Kinases

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 1. kinases phosphorylate and dephosphorylate proteins, turning them on and off
a. key proteins of the cell cycle that initiate or regulate DNA replication,
mitosis, and cytokinesis
2. cyclins switch kinases on and off at appropriate times
a. kinases have to be bound to cyclin before they become active
i. cyclin dependent protein kinases (Cdks)
b. cyclin also helps direct Cdk to its target proteins
i. determine which proteins are phosphorylated by Cdk
ii. cyclin is a regulatory subunit that determines the Cdk’s
specificity for particular substrates (target proteins)
3. cyclin concentrations vary in a cyclical fashion during the cell cycle
a. raises and lowers the amount of active Cdk-cyclin complexes
i. activity of complex rises and falls w/ each cycle, but the
concentration of Cdk doesn’t change
B. Cyclin-dependent Protein Kinases (Cdks) Are Regulated by the Accumulation and
Destruction of Cyclins

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1. M-cyclin (aka B-cyclin): the cyclin that helps drive cells into M-phase

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i. M-Cdk: complex of M-cyclin and Cdk

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ii. synthesis of M cyclin starts immediately after cell division

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iii. peak of M cyclin concentration is during mitosis

o.
iv. rapid decrease of M cyclin concentration at the end of mitosis
rs e v. called B-cyclin b/c of B-type??
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2. ubiquitination of the cyclins on M-Cdk mark it for destruction
a. w/o the cyclin, Cdk is inactivated
b. anaphase promoting complex (APC) add ubiquitin to Cyclins
o

i. APC activity is switched on late in mitosis in a process that

aC s

requires the activity of M-Cdk

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M-Cdk contributes to its own eventual inactivation

C. Cdk Activity is Regulated by Phosphorylation and Dephosphorylation
1. M-Cdk must be phosphorylated at sites that are required for activity
2. M-Cdk must also have inhibitory phosphates removed by phosphatase in order
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to become activated
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3. activated M-Cdk indirectly activates more M-Cdk

a. activates more activating phophatase
b. inhibits inhibitory kinases
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D. Different Cyclin-Cdk Complexes Trigger Different Steps in the Cell Cycle

1. Different Cyclins expressed during different stages
Th

a. G1 cyclin: act early in G1 driving cell through G1 toward S

b. S cyclin: bind to Cdk late in G1 triggering entry into S phase
c. M cyclin: acts in G2 to trigger M phase
2. concentration of each cyclin rises gradually and then falls sharply
sh

a. slow accumulation of cyclin helps control system measure time

intervals b/n one cell-cycle step to the next
3. Different classes of cyclins expressed at different stages of the cell cycle,
phosphorylate different proteins and activate different cellular processes
(different cyclin-Cdk complexes phosphorylate different proteins in the cell)
a. S-Cdk: proteins bound to replication origins (initiator proteins)

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 i. causes replication to start
b. M-Cdk (B-Cdk): condensins (condense chromosomes), lamin proteins
(causing breakdown of nuclear lamina), microtubule associated
proteins (causing formation of mitotic spindle) **all processes
involving mitosis
c. G1-Cdk: gene regulatory proteins (activating transcription of genes
needed for S phase/DNA replication)
i. ex: DNA polymerase
4. interregulation: what determines how much of and which cyclins are present?
a. regulated through phosphorylation
i. addition of phosphates by kinases
ii. removal of phosphates by phosphatases
b. as M phase cyclin goes up, S phase cyclins go down
c. as M cyclin activity is increasing you can get auto-activation
i. occurs through phosphorylation
ii. phosphorylates itself increasing amount of activated M cyclin

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d. high enough M cyclin activates G1 cyclin activity

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i. turn down M phase cyclins

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5. cyclin activity is regulated by . . .

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a. destruction of cyclin

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b. phosphorylation
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c. inhibitor proteins (cyclin dependent inhibitors, Cdi)
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i. bind to Cdk-cyclin complexes
E. S-Cdk Initiates DNA Replication and Helps Block Rereplication
1. origin recognition complex (ORC): binds to replication origins (where DNA
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replication starts) throughout the entire cell cycle

aC s

a. serves as a landing pad for other regulatory proteins that bind before
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the start of S phase

2. Cdc6, a GRP, binds to ORCs in G1 promoting the binding of other proteins
a. forms pre-replicative complex
3. S-Cdk is then activated, triggering the initiation of DNA replication
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4. S-Cdk also prevents rereplication of DNA

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a. phosphorylates Cdc6 which dissociates from the origin and is degraded

i. prevents replication from occurring at the same origin
b. phosphorylation of S-Cdk marks Cdc6 for ubiquitination & degradation
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F. Cdks Are Inactive Through Most of G1

1. At the end of mitosis all Cdk activity in the cell is reduced to zero
Th

a. S-Cdks are inactivated by destruction of S-cyclin at the end of S phase

b. M-Cdk is inactivated by destruction of M-cyclin toward end of mitosis
2. Cdks then remain inhibited throughout most of G1
a. Cdk-inhibitory proteins (cdis) prevent reactivation of Cdk during G1
sh

b. delay progression into next S phase, allowing cell time to grow

3. G1 cyclins must accumulate to end inhibitory state
a. G1 accumulation is stimulated by the extracellular signals that promote
cell proliferation
G. The Cell-Cycle Control System Can Arrest the Cycle at Specific Checkpoints
1. if one step is delayed, the control system delays the activation of the next steps

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 i. normal sequence is maintained
2. cell cycle can be stopped at specific checkpoints, allowing the cell to monitor its
internal state and environment before continuing w/ cycle
3. checkpoint proteins delay the cycle in response to damage
a. ex: break in chromosome
b. give cycle time to repair itself
4. ex: DNA damage causes an increase in the concentration and activity of p53, a
GRP/checkpoint protein (that is normally rapidly degraded)
a. p53 becomes active as a GRP (transcriptional activator) b/c it is
phosphorylated by kinases that are activated in response to DNA
damage
i. p53 accumulates and stimulates the transcription of the gene
that encode Cdi, p21
p21 binds to and inactivates G1/ S-Cdk and S-Cdk
-prevents cell from entering S phase
p21 is a Cdk inhibitor protein that stops cycle in early

m
er as
G1 until damage is repaired
d. p53/p21 is inactivated after cell damage is repaired

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i. can continue on w/ cell cycle
H. Cells Can Dismantle Their Control System and Withdraw from the Cell Cycle

o.
1. mammalian cells will multiply only if they are stimulated to do so by signals
rs e
from other cells
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2. if no signals: the cell cycle stops at the G1 checkpoint and enters G0
a. G0: modified G1 state in which the cell-cycle control system is largely
dismantled; cyclins and Cdks basically disappear
o

3. when proliferation is stimulated, cells reproduce cell-cycle control system, exit

aC s

G0, enter G1, and proceed w/ the cell cycle

vi y re

4. G1 checkpoint (aka G1 transition or Start/stop decision) offer cells a crossroad

a. complete another cycle: go on to S1
b. pause temporarily until conditions are right: arrest in G1
c. withdraw from the cell cycle altogether: enter G0
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III. Programmed Cell Death (Apoptosis)

ar stu

A. Overview
1. apoptosis: if cells are no longer needed, they commit suicide by activating an
intracellular death program
is

a. mostly related to cancer but also involves signal transduction pathways

and cell division
Th

2. cell death exactly balances cell division

a. otherwise tissue would grow or shrink
B. Mediated by an Intracellular Proteolytic Cascade
sh

1. apoptosis kills cells neatly, w/o damaging its neighbors

a. no cell necrosis (death from injury or damage to cell)
i. necrosis occurs when cells are sheared and spill contents
b. cytoskeleton and nuclear envelope collapse and are packaged into
vesicles (similar to prometaphase)
2. reasons for apoptosis

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 a. eliminates tissue b/n developing digits
a. embryo is a ball of cells that is sculpted by apoptosis
i. determines morphology/shape of organism
b. more than 50% of neurons die soon after being formed
c. response to unrepairable DNA damage
i. organism must destroy the cell before the damage DNA
becomes mutagenic for other cells; apoptosis is a last
resort
2. apoptosis is carried out by a family of proteases called caspases
a. caspases are start out as inactive procaspases
i. activated when cleaved by another member of the caspases
family in response to signals that induce apoptosis
b. activated caspases cleave/activate other family members, amplifying
the proteolytic cascade
c. caspases can also cleave other key proteins
i. ex: lamin proteins causing breakdown of nuclear lamina

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3. apoptotic cell shrinks and condenses and attracts phagocytic cells that engulf

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the dying cell before it can spill its connects on other cells (causing cell

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necrosis)

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a. phagocytic cells recognize cells surface signals from apoptotic cells

o.
C. Death Program is Regulated by the Bcl-2 Family of Intracellular Proteins
rs e
1. death program is irreversible; needs to be tightly regulated
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2. Bcl-2 intracellular proteins regulate the activation of procaspases
a. Bax and Bak are proteins that promote death
i. form channels in mitochondrial membrane
o

ii. cytochrome c is released into the cytosol

aC s

iii. cytochrome c binds to an adaptor protein that promotes

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aggregation and activation of a particular procaspase

molecule
iv. activated caspases triggers caspases cascade = apoptosis
b. Bcl-2 inhibits procaspase activation and apoptosis
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i. block ability of Bax and Bak to release cytochrome c from mitoc.

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c. other death factors bind to Bcl-2 and other death-suppressors in

order to promote apoptosis
D. Summary: 3 Signal Transduction Pathways of Apoptosis
is

1. Death factors signal lots of cells to die

a. ex: FAS
Th

b. FAS binds to a FAS receptor on the cell and changes procaspase 8 into
caspase 8 (activates it)
2. Survival factors tell cells not to go through apoptosis
a. ex: insulin like growth factor IGF
sh

b. IGF binds to IGF receptors on cell, stimulates Bcl-2, which prevents

the release of cytochrome C from the mitochondria that
accompanies apoptosis
c. if no survival factors are present cytochrome C is released from
mitochondria and triggers APAF 1
i. APAF 1 activates procaspase 9 into caspases 10

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 3. if there is unrepairable damage (usually to DNA) P53 deactivates the survival
factor Bcl-2, so that it is unable to prevent apoptosis
IV. Extracellular Control of Cell Numbers and Cell Size
A. Animal Cells Require Extracellular Signals To Divide, Grow, and Survive
1. organ and body size are determined by growth, division, and death of cells
a. all of which are regulated by signals from other cells combined w/
programs unique to the individual cell
2. extracellular signals that act positively to stimulate processes are of 3 types
(sometimes referred to universally as growth factors)
a. mitogens: stimulate cell division
i. overcome mechanisms that block progression of cell cycle
b. growth factors: stimulate cell growth (increase in cell mass)
i. promote the synthesis and inhibit the degradation of proteins
c. survival factors: promote cell survival by suppressing apoptosis
B. Mitogens Stimulate Cell Division
1. mitogens stimulate cell proliferation by inhibiting Rb protein

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a. Rb protein: retinoblastoma protein

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i. intracellular molecular brake that blocks the transition from G1

co
to S phase

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ii. binds to E2F, a GRP and transcription factor

o.
prevents E2F from stimulating the
rs e transcription of genes required for cell
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proliferation
b. mitogens bind to cell surface receptors and activate intracellular
signaling (kinase) pathways that lead to the phosphorylation and
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activation of the G1-Cdk and G1/S-Cdk

aC s

i. RTKs can activate inactive G1-Cdks by phosphorylation

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ii. these Cdks phosphorylate/inactivate Rb protein

E2F is now free to start transcription of S phase genes,
leading to cell proliferation
2. platelet-derived growth factor (PDFG) is a mitogen
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a. platelets in blood clots are triggered to release PDGF

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i. PDGF is an endocrine signal (moves through blood) stimulating

growth and immune system cells
b. PDGF binds to receptor tyrosine kinases (RTKs) in surviving cells at
is

the wound site stimulating them to proliferate and heal the wound
C. Extracellular Growth Factors Stimulate Cells to Grow
Th

1. cell growth depends on signals from other cells, but does NOT depend on the
cell-cycle control system
2. growth factors bind to cell surface receptors, activating various intracellular
sh

signaling pathways that lead to the accumulation of

proteins/macromolecules
a. increase the rate of protein synthesis
b. decrease the rate of protein degradation
3. some extracellular signals, like PDGF, act as both growth factors and mitogens
a. stimulate cell growth and cell-cycle progression

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 b. ensure that cells maintain their appropriate size as they proliferate
D. Animal Cells Require Survival Factors to Avoid Apoptosis
1. survival factors are signals sent from other cells telling a particular cell to live
a. if factors are missing, cell undergoes apoptosis
2. survival factors bind to cell surface receptors, activating intracellular signaling
pathways that keep the death program suppressed
a. regulate the # of Bcl-2 family proteins
i. increase production of apoptosis-suppressing Bcl-2 members
E. Some Extracellular Signal Proteins Inhibit Cell Growth, Division or Survival
1. some extracellular signal proteins act to inhibit tissue growth
a. oppose positive regulators (mitogens, growth/survival factors)
2. ex: myostatin is a signal protein that inhibits growth and proliferation of
myoblasts that form muscle
a. w/o gene muscles become several times larger than normal
i. both # and size of muscles is increased
makes huge cows!

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