Download Classes of cyclins

THE CELL CYCLE AND
PROGRAMED CELL DEATH
The minimum set of processes that a cell has to
perform are those that allow it to pass on its genetic
information to the next generation of cells
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Universal characteristics of cell cycle
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The two major phases of the cell cycle
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The eucaryotic cell cycle is traditionally
divided into four sequential phases
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Two functional phases, S and M phases
Two preparatory phases, G1 and G2
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Two functional phases, S and M
phases
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S phase:
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The phase in which the DNA is replicated.
The time it takes a typical human cell to complete S
phase is about 8 hours and is invariant under normal
circumstances.
M phase:
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Fully replicated chromosomes are segregated to each
of the two daughter nuclei by the process of mitosis.
The length of M phase is about 1 hour and is also
normally invariant.
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Two preparatory phases, G1 and G2
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G1 phase precedes S phase, whereas G2 phase
precedes M phase.
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G1 and G2 phases are required for the synthesis of
cellular constituents needed to support the following
phase and ultimately to complete cell division.
In mammalian cells, the length of G1 phase is highly
variable and can range from about 6 hours to several
days or longer.
The length of G2 phase is about 2 hours.
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Two preparatory phases, G1 and G2
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The cell monitors the internal and external
environment
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If extracellular conditions are unfavourable:
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When conditions are suitable and preparations are
complete the cell commits itself to S or M phase.
cells delay progress through G1 and may even enter a
specialized resting state known as G 0 (G zero).
Such cells are metabolically active, but are not actively
proliferating.
If extracellular conditions are favourable:

cells in early G1 or G0, become committed to DNA
replication, even if the extracellular signals that
stimulate cell growth and division are removed
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CELL-CYCLE CONTROL
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A successful cell division cycle requires the orderly
and unidirectional transition from one cell-cycle
phase to the next.
Certain events must be completed before others are
begun.

For example, beginning mitosis before the completion of
DNA replication would obviously be deleterious to the cell.
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Two classes of cell cycle regulatory
circuits exist
1.
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Intrinsic regulatory pathways:
Responsible for the precise
ordering of cell-cycle events.
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for example, entry into mitosis must
always come after DNA replication.
A clock, or timer, that turns on
each event at a specific time
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It provides a fixed amount of time
for the completion of each event.
Predominate in the transitions
between S, G2, and M phases in
mammalian cells because there
time is relatively invariant.
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Deregulation of intrinsic regulatory
pathways can contribute to cancer
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For example, errors in the
spindle-assembly checkpoint
can lead to chromosomal
imbalance and aneuploidy, a
feature characteristic of
virtually all cancers.
Misregulation of proteins that
control this checkpoint has
been detected in human
cancer
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Two classes of cell cycle regulatory
circuits exist
2.
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Extrinsic regulatory
pathways:
Function in response to
environmental conditions or in
response to detected cellcycle defects.
In these pathways, differences
between normal and neoplastic
cells are most commonly
observed.
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The cell cycle control system is a
protein kinase based machine
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The cell cycle control system is based on
two families of proteins:
1.
2.
Cyclin-dependent protein kinase (Cdk)
 Selectively phosphorylates downstream
proteins on serines and threonines
The specialized activating proteins (cyclins)
 They bind to Cdk molecules and control
their ability to phosphorylate target
proteins
 They undergo a cycle of synthesis and
degradation in each division cycle of the
cell
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Classes of cyclins:
1.
2.
3.
4.
G1/S-cyclins bind Cdks at
the end of G1 and commit
the cell to DNA replication.
S-cyclins bind Cdks during
S phase and are required
for the initiation of DNA
replication.
M-cyclins promote the
events of mitosis.
In most cells, a fourth class
of cyclins, the G1-cyclins,
helps promote passage
through Start or the
restriction point in late G1.
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Classes of Cdk protein
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In yeast cells A single Cdk protein binds all
classes of cyclins
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It drives all cell-cycle events by changing cyclin
partners at different stages of the cycle.
In vertebrate cells, by contrast, there are four
Cdks.
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Two interact with G1-cyclins
One interacts with G1/S- and S-cyclins
One interacts with M-cyclins.
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The names of the individual Cdks and cyclins
CYCLIN-CDK
COMPLEX
VERTEBRATES
BUDDING YEAST
CYCLIN
CDK PARTNER
CYCLIN
CDK PARTNER
G1-Cdk
cyclin D*
Cdk4, Cdk6
Cln3
Cdk1**
G1/S-Cdk
cyclin E
Cdk2
Cln1, 2
Cdk1
S-Cdk
cyclin A
Cdk2
Clb5, 6
Cdk1
M-Cdk
cyclin B
Cdk1**
Clb1, 2, 3, 4
Cdk1
* There are three D cyclins in mammals (cyclins D1, D2, and D3).
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Regulation of Cdk activity at different
stages of cell cycle:
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Phosphorylation/Dephosphorylation at a
pair of aa in the roof of the active site:
•
This regulatory
mechanism is
particularly important
in the control of MCdk activity at the
onset of mitosis.
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Cdk inhibitor proteins (CKIs) bind to and
regulate Cyclin-Cdk complexes
•
There are a variety of
CKI proteins that are
primarily employed in
the control of G1 and
S phase.
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The Cell-Cycle Control System Depends
on Cyclical Proteolysis
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Two ubiquitin ligases are important in the
destruction of cyclins and other cell-cycle
regulators:
1.
SCF enzyme complex responsible for the ubiquitylation
and destruction of:
–
2.
G1/S-cyclins and certain CKI proteins that control
S-phase initiation
The anaphase-promoting complex (APC) In M phase, is
responsible for the ubiquitylation and proteolysis of:
–
M-cyclins and other regulators of mitosis
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