Download cell death

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The cell cycle and cell death
The cell cycle: cells duplicate their
contents and divide
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The cell cycle may be divided into 4
phases
• Eucaryotic cell
division:
– Mitosis (nuclear
division)
– Cytokinesis (cell
division)
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The cell cycle triggers essential
processes (DNA replication, mitosis)
•Cell cycle 1 direction
•Irreversible
•Checkpoint
Invertebrate egg andXenopus
sea urchin, starfish, clam
M
Only S and M phase
no G1 or G2 phase
S
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Zygote cell division without growth
Somatic cells
Embryonic cells
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12 cycles of embryonic cells
General somatic cell cycle
G1
0
3
S
6
9
12
G2
15
18
M
21
24
time
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Figure 17-5 Molecular Biology of the Cell (© Garland Science 2008)
Progression of the cell cycle is regulated by
feedback from intracellular events
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Cyclin-dependent protein kinases drive progression
through the cell cycle
• Cyclin-dependent kinases (Cdks) are inactive
unless bound to cyclins
• Active complex phosphorylates downstream
targets
• Cyclin helps to direct Cdks to the target proteins
• Full activation of the cyclin-Cdk complex then
occurs when a separate kinase, the Cdkactivating kinase (CAK), phosphorylates an amino
acid near the entrance of the Cdk active site
Distinct cyclins partner with distinct Cdks
to trigger different events of the cell cycle
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4 classes
of cyclins
G1/S-cyclins
• activate Cdks
in late G1 
trigger
progression
through
Start,
• commitment
to cell-cycle
entry
G1/SCdk
Vertebrates
S-cyclins
• stimulate
chromosome
duplication.
• S-cyclin levels
remain
elevated until
mitosis,
• control some
early mitotic
events.
S-Cdk
Vertebrate
Cyclin E
Cyclin A
Cdk2
Cdk2, Cdk1
Yeast
Yeast
Cln1,2
Clb5,6
Cdk1
Cdk1
M-cyclins
G1-cyclins
• activate
Cdks that
stimulate
entry into
mitosis at
the G2/M
checkpoint.
M-Cdk
Vertebrate
Cyclin B
Cdk1
Yeast
Cdk1
G1-Cdk
• govern the
activities of
the G1/S
cyclins,
which
control
progression
through
Start in late
G1
Vertebrate
Cyclin D
Cdk4, Cdk6
Yeast
Cln3
Cdk1
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Cyclin levels during the cell cycle
• Phosphorylation by a protein kinase  inhibit
cdk activity : i.e. wee vs cdc25
• Binding to cdk inhibitor proteins
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Cell cycle control is regulated by protein
degradation
•
•
•
•
•
Another cell-cycle control
system: SCF
Ubiquitylates CKI proteins
M-cyclin becomes covalently modified by addition of multiple copies of
ubiquitin at the end of mitosis
Ubiquitylation mediated by the anaphase promoting complex (APC)/
cyclosome
Ubiquitination marks cyclins for destruction by large proteolytic machines
called proteasome
Multiple mechanism regulate Cdk activity
Checkpoints ensure the cell cycle proceeds without errors
Figure 17-21 Molecular Biology of the Cell (© Garland Science 2008)
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S-phase
• Chromosome Duplication  1 x
/cell cycle  regulation
prereplicative complex and
preinitiation complex vs S-Cdk
Step 1
Step 2
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Figure 17-22 Molecular Biology of the Cell (© Garland Science 2008)
M-Phase
• Mitosis regulatory
– Abrupt increase in M-Cdk
activity at the G2/M
checkpoint  triggers
early mitosis (prophase,
metaphase)
– APC/C triggers
desctruction of securin,
liberating a protease that
cleaves cohesin  initiates
separation of the sister
chromatids
Figure 17-44 Molecular Biology of the Cell (© Garland Science 2008)
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Mitotic entry is
triggered by a steep
increase in cyclin B–
CDK1 activity and
both PLK1 and
aurora kinase A can
contribute to this
crucial event
Crosstalk between PLK1 and
aurora kinase B in the regulation of
kinetochore–microtubule
interactions
Emie & Medema, 2010
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Dephosphorylation activates M-Cdk at
the onset of Mitosis
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cohesin
condensin
Chromosome Dynamics Laboratory | Tatsuya Hirano | RIKEN Advanced Science Institutewww.asi.riken.jp
(Hagstrom & Meyer, 2003)
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Figure 17-28 Molecular Biology of the Cell (© Garland Science 2008)
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Checkpoint: spindle assembly
• Mitosis must not complete unless all the
chromosomes are attached to the mitotic spindle
• Mitotic checkpoint delays metaphase to
anaphase transition until all chromosomes are
attached
• Prolonged activation of the checkpoint -->cell
death
Figure 18.35 Relation of centrosome duplication to the cell cycle.
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Molecular Biology of the Cell (© Garland Science 2008)
Control of cell division and cell growth
• Mitogens,
– stimulate cell division, primarily
by triggering a wave of G1/S-Cdk
activity that relieves intracellular
negative controls that otherwise
block progress through the cell
cycle.
• Growth factors,
– stimulate cell growth (an increase
in cell mass) by promoting the
synthesis of proteins and other
macromolecules and by inhibiting
their degradation.
• survival factors,
– promote cell survival by
suppressing the form of
programmed cell death known as
apoptosis.
Figure 17-62 Molecular Biology of the Cell (© Garland Science 2008)
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Figure 17-65 Molecular Biology of the Cell (© Garland Science 2008)
Limitation cell number and cell cycle arrest
• Limitation cell number
– Replicative cell senescence
• Abnormal proliferation signals cause cell cycle
arrest
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Checkpoint: DNA damage arrests
the cell cycle in G1
Cells can withdraw from the cell
cycle and dismantle the regulatory
machinery
• G0 is a quiescent state
• Cdks and cyclins disappear
• Some cells enter G0 temporarily and divide
infrequenty (I.e. hepatocytes)
• Other differentiated cell types (neurons)
spend their life in G0
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CELL DEATH
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Apoptosis vs. necrosis
Necrotic cell
Apoptotic cells
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Apoptosis
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Melino et al.2005
Different types of programmed cell death. Morphologically distinct types of cell death. At least 11 different types of cell death are
known, 10 of which procede according to genetically programmed mechanisms. Some forms of death are not considered separately
since they are identical to those indicated, that is, oncosis is a form of necrosis, and anoikis is apoptosis triggered by cell detachment.
This does not exclude the possibility of additional mechanisms in higher or lower organisms such as in bacteria and Dictyostelium.
The columns indicate, in a very simplified and schematic way, the different characteristics of the different forms of death, and in
particular the findings in the plasma membrane, the nucleus, the mitochondria, and other cytosolic organelles. The details are only
indicative, and are presented especially to highlight the differences between apoptosis, autophagy and cornification (boxes), which
are discussed in detail in this special issue of Cell Death Differentiation. WD, Wallerian degeneration; PLT, platelets; TG,
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transglutaminases; NO, nitric oxide; NCX, sodium calcium exchange channel; IAP, inhibitor of apoptosis proteins
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Pathogen-induced host cell death.
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Apoptosis: the necessity for cell death
in multicellular organisms
• Embryonic morphogenesis
• Killing by immune effector cells
• Wiring of the developing nervous
system
• Regulation of cell viability by hormones
and growth factors (most cells die if
they fail to receive survival signals from
other cells)
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Developmentally-regulated
apoptosis
Apoptosis: regulation of apoptosis
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Figure 1. Cell death outcomes following fungal pathogen attack.
Dickman MB, de Figueiredo P (2013) Death Be Not Proud—Cell Death Control in Plant Fungal Interactions. PLoS Pathog 9(9):
e1003542. doi:10.1371/journal.ppat.1003542
http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003542
Cell death modalities in response
to infection. Diagram
representing some of the
characteristic features of different
types of programmed cell death
that can occur in response to
infection in plants and mammals.
HR cell death in plants (a) and
pyroptosis (b) and Necroptosis
(c) in mammalian cells. See the
text for details
Coll, P Epple and J L Dangl, 2011
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