Fundamentals of Cell Biology Chapter 13: The Birth and Death of Cells

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Fundamentals of Cell BiologyChapter 13 The
Birth and Death of Cells
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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

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Frequency of cell division

• Frequency of cell division varies by cell type
• embryo
• cell cycle lt 20 minute
• skin cells
• divide frequently throughout life
• 12-24 hours cycle
• liver cells
• retain ability to divide, but keep it in reserve
• divide once every year or two
• mature nerve cells muscle cells
• do not divide at all after maturity
• permanently in G0

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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

Theres noturning back, now!
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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

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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?

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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

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G0 phase

• G0 phase
• non-dividing, differentiated state
• most human cells in G0 phase

• liver cells
• in G0, but can be called back to cell cycle by
  external cues
• nerve muscle cells
• highly specialized
• arrested in G0 can never divide

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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?
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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
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Cyclins Cdks

• Interaction of Cdks different cyclins triggers
  the stages of the cell cycle

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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

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Cell cycle signals

• Cell cycle controls
• cyclins
• regulatory proteins
• levels cycle in the cell
• Cdks
• cyclin-dependent kinases
• phosphorylates cellular proteins
• activates or inactivates proteins
• Cdk-cyclin complex
• triggers passage through different stages of cell
  cycle

inactivated Cdk
activated Cdk
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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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To start

• You need signals gtgtgtgtgt

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Cell cycle step 1 Signal transduction initiates
cell cycle progression.
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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
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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 pro- teins. 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
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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
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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
self-destruct 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
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Targets of pro- and anti-apoptotic transcription
factors are members of bcl-2 family
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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-to-anaphasetransition 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