Cell proliferation and its regulation
Significance:
1,For the growth and development of a multicellular
organism,and for the generation of offspring;
2,Produce new organisms in unicellular species;
3,Renew the aging,apoptotic cells,and damaged tissue;
So,cell proliferation is one of the most
important characters for life
Chapter 11
If damaged
seriously by UV,
mouse will die
within several
days.
1,The cell cycle
A,Overview of the cell cycle
The most basic function of the cell cycle is to duplicate accurately
the vast amount of DNA in the chromosomes and then segregate
the copies precisely into two genetically identical daughter cells.
?Cell cycle phases:
?Interphase,G1-S-G2
?M phase,Mitosis,Cytokinesis
?Different cell cycle length
Some eukaryotic cell cycle times
The greatest variation occurs in the duration of G1
The shortest eukaryotic division cycles of all are
the early embryonic cell cycles,no G1 and G2
?Biochemical events of cell cycle
G1 phase,Synthesize proteins (RNA) for the DNA
replication,Uncondense chromatin.
S phase,Synthesis of DNA and Histones
G2 phase,Synthesis of a few proteins (RNA)
M phase,Mitosis and meiosis and cytokinesis
Two daughter cells
Chromosome condense Mitotic spindle Contractile ring
?Three categories of cells in vivo
(1) Cycling cells
Dividing continuously—Stem cells
(2) G0 cells
Do not divide normally,but divide when given an
appropriate stimulus,liver cells,lymphocytes
(3) Terminally Differentiated cells
Highly specialized,have lost the ability to divide
until they die,muscle cells,red blood cells,nerve cells
Embryo cells
Cycling
cells
G0
cells
Terminal
cells
B,Synchronization of cell (for cell population)
(1) Natural synchronization
Early embryo in most invertebrates and a few
vertebrates
Fruit fly
embryo
(2) Selected synchronization artificially
Isolation of cells in M phase
Isolation of cells by centrifugation
(3) Synchronization of cells induced by drugs
Blocking DNA synthesis by TdR
G1/S—TdR
G1
SG2
M G1/S
Blocking cells in metaphase by colchicine
Affect the assembly of mitotic spindle
Special cell cycles—
Early embryo (30min/cell cycle)
(1) No G1 and G2 phase,all replicons are activated,
so S phaseis very short
(2) Have little or no need to synthesize components
other than DNA,cell division
(3) No cell growth during cell cycle
Frog Xenopus laevis
2,Mitosis
(1) Prophase
?Chromatins condense to form compacted mitotic
chromosomes
Activated M-Cdk
phosphrylates condensin
subunits,triggering the
assembly of condensin
complexes on DNA and
condensation of the
chromosome,
The condensin can use
energy of ATP
hydtolysis to promote
DNA coiling(in vitro).
The sister
chromatids are glued
together by
multisubunit protein
complex called
cohesins.
? Centrosome duplicated at
S,and separate to form
mitotic spindle at the
beginning of prophase
Assembly of
kinetochore at
the end of
prophase
?Golgi,ER etc,disperse
to form vesicles;
kinetochore assembly
Schematic representation of the kinetochore
(2) Prometaphase
?Nuclear envelopes breakdown (Lamin
phosphorylation)
?Spindle MTs capture chromosomes
?The pushing and pulling forces drive the
chromosomes to the metaphase plate
.
MT behavior during formation of the
metaphase plate,Initially,MT from
opposite poles are different in length.
Experimental demonstration of the
importance of mechanical tension
in metaphase checkpoint control.
(3) Metaphase
All chromosomes align at metaphase plate
Microtubules are highly dynamic in the
metaphase spindle.
?The events of Anaphase,Both anaphase A and
anaphase B contribute to the movement of chromosome
toward the spindle poles
Anaphase A,The movement of the chromosomes toward the poles; Kinetochore
MT disaassenble at both ends during anaphase A.
Anaphase B,The two spindle poles move farther apart,Both pushing and pulling
forces contribute to anaphase B
(4) Anaphase
?Anaphase B,The two spindle poles move
farther apart.
The sliding of
overlap MT at
anaphase.
Metaphase Late anaphase
?A model explains the chromosome
movement in anaphase
Two alternative models of how the kinetochore may generate
a poleward force on its chromosome during anaphase A.
?The control of Anaphase,SCF and APC activities
during the cell cycle
Cdc20 and cdh1 are subunits to binding APC,APCcdc20 becomes activated at the metaphase/anaphase transition,
Securin,anaphase inhibitor,The destruction of securin by proteasomes at the end of metaphase starts a train
reaction that leads to the cleavage of the cohesin complex,Cohesin holds sister chromatids together,Destruction of
cohesin triggers the separation of two chromatids.
Cohesin
细胞周期中 SCF与 APC的活性。 SCF和 APC是多亚基复合体，它们将底物蛋白泛素化，致使底物
由蛋白酶体降解。（ a） SCF主要在间期有活性，而 APC主要在有丝分裂期有活性。 APC有两种，
它们的区别在于分别含 Cdc20或 Cdh1亚基，亚基改变 APC识别的底物。有丝分裂中,APCCdc20比
APCCdh1早激活。 （ b） APCCdc20负责降解抑制后期的蛋白，如 securin，它们的降解促使细胞由中
期转至后期。 APCCdh1负责蛋白泛素化（如 M-cyclin）,M-cyclin抑制细胞脱离有丝分裂，泛素化
底物蛋白的降解促使细胞 M-G1期转换。
The spindle checkpoint(mammalian cell
in late prometaphase labeled with
anibodies against the spindle checkpoint
protein Mad2 and tubulin).
Mad2
?The spindle-attachment checkpoint,
Anaphase is delayed until all chromosoms are
positioned at the metaphase plate
已发现 Mad2与 Cdc20结合，抑制 APC的激活 ;只有当 Mad2分子从所有的染色体上失去后,APC才
能被激活，后期才能开始,
(5) Telophase
Chromosome uncondense
Nuclear envelope reforms around
individual chromosome
Golgi,ER reconstruct
Nucleolus reassemble
Mitosis
ends
3,Cytokinesis
(1) In animal cells
The MT of mitotic spindle determine the plane of animal
cell division; Mitosis can occur without cytokinesis,
?Contractile ring,Actin and myosinII in the
contractile ring generate the force for cytokinesis
(2) In plant cells,The phragmoplast guides cytokinesis in
higher plants;
The assembly of the cell plate begins in late anaphase and is guided by
phragmoplast
4,Meiosis
?The comparison of
meiosis and mitosis
?Two major
contributions to
the reassortment
of genetic
material that
occurs in the
production of
gametes during
meiosis.
Visible evidence of crossing over
?Comparison of
the mechanisms of
chromosome
alignment (at
metaphase) and
separation (at
anaphase) in
meiotic division I
and meiotic
division II.
?Meiotic chromosome pairing culminates in the
formation of the synaptonemal complex
?Influence of
Sry on gonad
development.
The stages of oogenesis and spermatogenesis
5,The cell-cycle control system
A,The cell-cycle control system triggers the major
processes of the cell cycle
B,The control system can arrest the cell cycle at
specific checkpoints
C,The cell cycle control system is based on cyclically
actived protein kinases---cyclin-dependent kinases
(Cdks),Engine molecules for cell cycle
G1checkpoint,fission yeast cells,Start point；
Animal cells,Restriction Point
D,MPF (Maturation-promoting factor，
Mitosis-promoting factor)
Lab,of
Toronto
Univ and
Yale Univ.
maturation
promoting
factor,
MPF
Purdue
Univ.:
Behavior
of MPF
The fusion of M-phase HeLa cell with Ptk cell (G1,S,G2)
inducing PCC,Exp,Demonstration that cells contain factors that
stimulate entry into mitosis.；
?The prematurely condensed chromosome (PCC)
MPF(M-Cdk):
p34cdc2
cyclinB{
Two subunits:
Catalytic subunit
transfers ~P from
ATP to Ser and
Thr;
Regulatory subunit
called cyclin
(Marine Biological
Lab.at Woods Hole
and UC Berkeley
Univ,of Oxford--yeast)
E,A simplified view of the core of the cell-cycle
conreol system
Cdk associates
successively with
different cyclins to
trigger the different
events of the cycle.
Cdk activity is
usually terminated
by cyclin
degradation.
Tree of cyclins are required in all eucaryotic cells:
1,G1/S-cyclins bind Cdks at the end of G1 and commit the cell to
DNA replication.
2,S-cyclins bind Cdks during S phase and are required for the
initiation of DNA replication.
3,M-cyclins promote the events of mitosis.
?The structural basis of Cdk activation
The human Cdk2 is shown in three states,(A) In the inactive,
without cyclin bound,the active site is blocked by a region of the
protein called the T-loop; (B) The binding of cyclin causes the T-
loop to move out of the active site,resulting in partial activition of
Cdk2; (C) Phosphorylation of Cdk2 by CAK at a threonine residue
in the T-loop,fully active.
?Cdk activity can be
suppressed both by inhibitory
phosphorylation (pp586:14.6)
and by inhibitory proteins
(CKIs).
P27—Cdk inhibitor proteins(CKIs)
?The cell-cycle control system depends on cyclical
proteolysis---The control of proteolysis by SCF and APC
during the cell cycle,(A)The phosphorylation of a
target protein(CKI),allows
the CKI to be recognized by
SCF (constitutive active),
E1and E2(two additional
proteins),SCF serves as a
ubiquitin ligase.The
ubiquitylated CKI is then
immediately recognized and
degraded in a proteasome.
SCF mediate the destruction
of G1-cyclins,Cdk
inhibitor,and other cell cycle
proteins.
(B)M-cyclin ubiquitylation
is performed by APC.
In G1 and S phase
In metaphase/anaphase
M-cyclins
F,Intracellular control of cell-cycle events
?S-phase Cyclin-Cdk complexes (S-Cdks) initiate DNA
replication once per cycle
Evidence from cell-fusion exp,For a replication block,
?The initiation of DNA
replication once per cell cycle.
ORC,origin recognition complex;
Cdc6,regulatory protein,it is present at
low levels during most of the cell cycle
but increases transiently in early
G1,where it is required for the binding
of a complex composed of a group of
closely related proteins,the Mcm
proteins.
?The activation of M-phase cyclin-Cdk complexes (M-
Cdks) triggers entry into mitosis
The activation of M-Cdk
?The DNA replication checkpoint,
Entry into mitosis is blocked by incomplete DNA
replication
The experiments of DNA replication checkpoint in the
mammalian cells in culture were treated with caffeine and
hydroxyurea.
?The spindle-attachment checkpoint,Unattached
chromosomes block sister-chromatid separation
?The sister chromatid separation is triggered by
proteolysis
The triggering of sister-
chromatid separation by the
APC.
APC,anaphase-promoting
complex
The destruction of Securin
allows separase to cleave
the cohesin complex.
Securin(后期抑制因子 )
separase
cohesin
1,Mad2 is normally localized at the kinetochores of
prometaphase and misaligned metaphase chromosomes,
Mad2 provides a,wait” signal that delays a cell’s progression
into anaphase,
The cell that possess mutant Mad2 fail to arrest at metaphase
when their chromosomes are misaligned.
Mad2 bind to Cdc20,inhibiting its activation of the APC,an
event that is required for the metaphase-to-anaphase
transition.
It is only after the Mad2 is absent from all of the
chromosomes that APC activation can occur and anaphase can
begin.
2,The cell that contains Monoattached chromosome delays the
onset of anaphase until the chromosome becomes a biattached
chromosome and aligned at the equator.
?Mad2 protein on unattached
kinetochores.
?Exit from mitosis requires the
inactivation of M-Cdk
?M-Cdk inactivation occurs
mainly by ubiquitin-dependent
proteolysis of M-cyclins
?The G1 phase is a state of stable Cdk inactivity
The creation of a G1 phase
by stable Cdk inhibition
after mitosis.
?The mechanisms cotrolling S-phase initiation in
animal cells.
?The Rb protein acts as a brake in mammalian G1 cells
?The control of G1 progression and S-phase initiation is
often disrupted in cancer cells,leading to unrestrained
cell-cycle entry and cell proliferation.
Mitogens stimulate G1-Cdk and G1/S-Cdk activities
A simplified model of one
way that mitogens stimulate
cell division
?DNA damage checkpoint,Cell-cycle progression is
blocked by DNA damage and p53
How DNA damage
arrests the cell cycle
in G1.
Two such checkpoints:
1.One in late G1,provents entry
into S phase;
2.One in late G2,provents entry
into mitosis;
P53,gene regulatory protein.DNA
damage activates p53 by an
indirect mechanism,
Mdm2 acts as a ubiquitin ligase
that targets p53 for destruction by
proteasomes,Phosphrylated p53
reduce its binding to Mdm2.
P21(CKI protein) binds to G1/S-
Cdk and S-Cdk and inhibits their
activities,thereby helping to block
entry into S phase.
?The summary of cell-cycle control system
Summary
An ordered sequence of cyclin-Cdk activities
triggers most of the events of the cell cycle,During
G1 phase,Cdk activity is reduced to a minimum by
Cdk inhibitors(CKIs),cyclin proteolysis,and
decreased cyclin gene transcription,When
environmental conditions are favorable,G1- and
G1/S-Cdks increase in concentration,overcoming
these inhibitory barriers in late G1 and triggering
the activation of S-Cdk,The S-Cdk phosphorylates
proteins at DNA replication origins,initiating DNA
synthesis through a mechanism that ensures that
the DNA is duplicated only once per cell cycle.
Once S-phase is completed,the activation of M-Cdk
leads to the events of early mitosis,whereby the cell
assembles a mitotic spindle and prepares for segregation
of the duplicated chromosomes---which consist of sister
chromatids glued together.
Ananphase is triggered by the destruction of the proteins
that hold the sisters together,The M-Cdk is then
inactivated by cyclin proteolysis,which leads to
cytokinesis and the end of M phase,Progression through
the cell cycle is regulated precisely by various inhibitory
mechanisms that arrest the cell cycle at specific
checkpoints when events are not completed successfully,
when DNA damage occurs,or when extracellular
conditions are unfavorable.
Significance:
1,For the growth and development of a multicellular
organism,and for the generation of offspring;
2,Produce new organisms in unicellular species;
3,Renew the aging,apoptotic cells,and damaged tissue;
So,cell proliferation is one of the most
important characters for life
Chapter 11
If damaged
seriously by UV,
mouse will die
within several
days.
1,The cell cycle
A,Overview of the cell cycle
The most basic function of the cell cycle is to duplicate accurately
the vast amount of DNA in the chromosomes and then segregate
the copies precisely into two genetically identical daughter cells.
?Cell cycle phases:
?Interphase,G1-S-G2
?M phase,Mitosis,Cytokinesis
?Different cell cycle length
Some eukaryotic cell cycle times
The greatest variation occurs in the duration of G1
The shortest eukaryotic division cycles of all are
the early embryonic cell cycles,no G1 and G2
?Biochemical events of cell cycle
G1 phase,Synthesize proteins (RNA) for the DNA
replication,Uncondense chromatin.
S phase,Synthesis of DNA and Histones
G2 phase,Synthesis of a few proteins (RNA)
M phase,Mitosis and meiosis and cytokinesis
Two daughter cells
Chromosome condense Mitotic spindle Contractile ring
?Three categories of cells in vivo
(1) Cycling cells
Dividing continuously—Stem cells
(2) G0 cells
Do not divide normally,but divide when given an
appropriate stimulus,liver cells,lymphocytes
(3) Terminally Differentiated cells
Highly specialized,have lost the ability to divide
until they die,muscle cells,red blood cells,nerve cells
Embryo cells
Cycling
cells
G0
cells
Terminal
cells
B,Synchronization of cell (for cell population)
(1) Natural synchronization
Early embryo in most invertebrates and a few
vertebrates
Fruit fly
embryo
(2) Selected synchronization artificially
Isolation of cells in M phase
Isolation of cells by centrifugation
(3) Synchronization of cells induced by drugs
Blocking DNA synthesis by TdR
G1/S—TdR
G1
SG2
M G1/S
Blocking cells in metaphase by colchicine
Affect the assembly of mitotic spindle
Special cell cycles—
Early embryo (30min/cell cycle)
(1) No G1 and G2 phase,all replicons are activated,
so S phaseis very short
(2) Have little or no need to synthesize components
other than DNA,cell division
(3) No cell growth during cell cycle
Frog Xenopus laevis
2,Mitosis
(1) Prophase
?Chromatins condense to form compacted mitotic
chromosomes
Activated M-Cdk
phosphrylates condensin
subunits,triggering the
assembly of condensin
complexes on DNA and
condensation of the
chromosome,
The condensin can use
energy of ATP
hydtolysis to promote
DNA coiling(in vitro).
The sister
chromatids are glued
together by
multisubunit protein
complex called
cohesins.
? Centrosome duplicated at
S,and separate to form
mitotic spindle at the
beginning of prophase
Assembly of
kinetochore at
the end of
prophase
?Golgi,ER etc,disperse
to form vesicles;
kinetochore assembly
Schematic representation of the kinetochore
(2) Prometaphase
?Nuclear envelopes breakdown (Lamin
phosphorylation)
?Spindle MTs capture chromosomes
?The pushing and pulling forces drive the
chromosomes to the metaphase plate
.
MT behavior during formation of the
metaphase plate,Initially,MT from
opposite poles are different in length.
Experimental demonstration of the
importance of mechanical tension
in metaphase checkpoint control.
(3) Metaphase
All chromosomes align at metaphase plate
Microtubules are highly dynamic in the
metaphase spindle.
?The events of Anaphase,Both anaphase A and
anaphase B contribute to the movement of chromosome
toward the spindle poles
Anaphase A,The movement of the chromosomes toward the poles; Kinetochore
MT disaassenble at both ends during anaphase A.
Anaphase B,The two spindle poles move farther apart,Both pushing and pulling
forces contribute to anaphase B
(4) Anaphase
?Anaphase B,The two spindle poles move
farther apart.
The sliding of
overlap MT at
anaphase.
Metaphase Late anaphase
?A model explains the chromosome
movement in anaphase
Two alternative models of how the kinetochore may generate
a poleward force on its chromosome during anaphase A.
?The control of Anaphase,SCF and APC activities
during the cell cycle
Cdc20 and cdh1 are subunits to binding APC,APCcdc20 becomes activated at the metaphase/anaphase transition,
Securin,anaphase inhibitor,The destruction of securin by proteasomes at the end of metaphase starts a train
reaction that leads to the cleavage of the cohesin complex,Cohesin holds sister chromatids together,Destruction of
cohesin triggers the separation of two chromatids.
Cohesin
细胞周期中 SCF与 APC的活性。 SCF和 APC是多亚基复合体，它们将底物蛋白泛素化，致使底物
由蛋白酶体降解。（ a） SCF主要在间期有活性，而 APC主要在有丝分裂期有活性。 APC有两种，
它们的区别在于分别含 Cdc20或 Cdh1亚基，亚基改变 APC识别的底物。有丝分裂中,APCCdc20比
APCCdh1早激活。 （ b） APCCdc20负责降解抑制后期的蛋白，如 securin，它们的降解促使细胞由中
期转至后期。 APCCdh1负责蛋白泛素化（如 M-cyclin）,M-cyclin抑制细胞脱离有丝分裂，泛素化
底物蛋白的降解促使细胞 M-G1期转换。
The spindle checkpoint(mammalian cell
in late prometaphase labeled with
anibodies against the spindle checkpoint
protein Mad2 and tubulin).
Mad2
?The spindle-attachment checkpoint,
Anaphase is delayed until all chromosoms are
positioned at the metaphase plate
已发现 Mad2与 Cdc20结合，抑制 APC的激活 ;只有当 Mad2分子从所有的染色体上失去后,APC才
能被激活，后期才能开始,
(5) Telophase
Chromosome uncondense
Nuclear envelope reforms around
individual chromosome
Golgi,ER reconstruct
Nucleolus reassemble
Mitosis
ends
3,Cytokinesis
(1) In animal cells
The MT of mitotic spindle determine the plane of animal
cell division; Mitosis can occur without cytokinesis,
?Contractile ring,Actin and myosinII in the
contractile ring generate the force for cytokinesis
(2) In plant cells,The phragmoplast guides cytokinesis in
higher plants;
The assembly of the cell plate begins in late anaphase and is guided by
phragmoplast
4,Meiosis
?The comparison of
meiosis and mitosis
?Two major
contributions to
the reassortment
of genetic
material that
occurs in the
production of
gametes during
meiosis.
Visible evidence of crossing over
?Comparison of
the mechanisms of
chromosome
alignment (at
metaphase) and
separation (at
anaphase) in
meiotic division I
and meiotic
division II.
?Meiotic chromosome pairing culminates in the
formation of the synaptonemal complex
?Influence of
Sry on gonad
development.
The stages of oogenesis and spermatogenesis
5,The cell-cycle control system
A,The cell-cycle control system triggers the major
processes of the cell cycle
B,The control system can arrest the cell cycle at
specific checkpoints
C,The cell cycle control system is based on cyclically
actived protein kinases---cyclin-dependent kinases
(Cdks),Engine molecules for cell cycle
G1checkpoint,fission yeast cells,Start point；
Animal cells,Restriction Point
D,MPF (Maturation-promoting factor，
Mitosis-promoting factor)
Lab,of
Toronto
Univ and
Yale Univ.
maturation
promoting
factor,
MPF
Purdue
Univ.:
Behavior
of MPF
The fusion of M-phase HeLa cell with Ptk cell (G1,S,G2)
inducing PCC,Exp,Demonstration that cells contain factors that
stimulate entry into mitosis.；
?The prematurely condensed chromosome (PCC)
MPF(M-Cdk):
p34cdc2
cyclinB{
Two subunits:
Catalytic subunit
transfers ~P from
ATP to Ser and
Thr;
Regulatory subunit
called cyclin
(Marine Biological
Lab.at Woods Hole
and UC Berkeley
Univ,of Oxford--yeast)
E,A simplified view of the core of the cell-cycle
conreol system
Cdk associates
successively with
different cyclins to
trigger the different
events of the cycle.
Cdk activity is
usually terminated
by cyclin
degradation.
Tree of cyclins are required in all eucaryotic cells:
1,G1/S-cyclins bind Cdks at the end of G1 and commit the cell to
DNA replication.
2,S-cyclins bind Cdks during S phase and are required for the
initiation of DNA replication.
3,M-cyclins promote the events of mitosis.
?The structural basis of Cdk activation
The human Cdk2 is shown in three states,(A) In the inactive,
without cyclin bound,the active site is blocked by a region of the
protein called the T-loop; (B) The binding of cyclin causes the T-
loop to move out of the active site,resulting in partial activition of
Cdk2; (C) Phosphorylation of Cdk2 by CAK at a threonine residue
in the T-loop,fully active.
?Cdk activity can be
suppressed both by inhibitory
phosphorylation (pp586:14.6)
and by inhibitory proteins
(CKIs).
P27—Cdk inhibitor proteins(CKIs)
?The cell-cycle control system depends on cyclical
proteolysis---The control of proteolysis by SCF and APC
during the cell cycle,(A)The phosphorylation of a
target protein(CKI),allows
the CKI to be recognized by
SCF (constitutive active),
E1and E2(two additional
proteins),SCF serves as a
ubiquitin ligase.The
ubiquitylated CKI is then
immediately recognized and
degraded in a proteasome.
SCF mediate the destruction
of G1-cyclins,Cdk
inhibitor,and other cell cycle
proteins.
(B)M-cyclin ubiquitylation
is performed by APC.
In G1 and S phase
In metaphase/anaphase
M-cyclins
F,Intracellular control of cell-cycle events
?S-phase Cyclin-Cdk complexes (S-Cdks) initiate DNA
replication once per cycle
Evidence from cell-fusion exp,For a replication block,
?The initiation of DNA
replication once per cell cycle.
ORC,origin recognition complex;
Cdc6,regulatory protein,it is present at
low levels during most of the cell cycle
but increases transiently in early
G1,where it is required for the binding
of a complex composed of a group of
closely related proteins,the Mcm
proteins.
?The activation of M-phase cyclin-Cdk complexes (M-
Cdks) triggers entry into mitosis
The activation of M-Cdk
?The DNA replication checkpoint,
Entry into mitosis is blocked by incomplete DNA
replication
The experiments of DNA replication checkpoint in the
mammalian cells in culture were treated with caffeine and
hydroxyurea.
?The spindle-attachment checkpoint,Unattached
chromosomes block sister-chromatid separation
?The sister chromatid separation is triggered by
proteolysis
The triggering of sister-
chromatid separation by the
APC.
APC,anaphase-promoting
complex
The destruction of Securin
allows separase to cleave
the cohesin complex.
Securin(后期抑制因子 )
separase
cohesin
1,Mad2 is normally localized at the kinetochores of
prometaphase and misaligned metaphase chromosomes,
Mad2 provides a,wait” signal that delays a cell’s progression
into anaphase,
The cell that possess mutant Mad2 fail to arrest at metaphase
when their chromosomes are misaligned.
Mad2 bind to Cdc20,inhibiting its activation of the APC,an
event that is required for the metaphase-to-anaphase
transition.
It is only after the Mad2 is absent from all of the
chromosomes that APC activation can occur and anaphase can
begin.
2,The cell that contains Monoattached chromosome delays the
onset of anaphase until the chromosome becomes a biattached
chromosome and aligned at the equator.
?Mad2 protein on unattached
kinetochores.
?Exit from mitosis requires the
inactivation of M-Cdk
?M-Cdk inactivation occurs
mainly by ubiquitin-dependent
proteolysis of M-cyclins
?The G1 phase is a state of stable Cdk inactivity
The creation of a G1 phase
by stable Cdk inhibition
after mitosis.
?The mechanisms cotrolling S-phase initiation in
animal cells.
?The Rb protein acts as a brake in mammalian G1 cells
?The control of G1 progression and S-phase initiation is
often disrupted in cancer cells,leading to unrestrained
cell-cycle entry and cell proliferation.
Mitogens stimulate G1-Cdk and G1/S-Cdk activities
A simplified model of one
way that mitogens stimulate
cell division
?DNA damage checkpoint,Cell-cycle progression is
blocked by DNA damage and p53
How DNA damage
arrests the cell cycle
in G1.
Two such checkpoints:
1.One in late G1,provents entry
into S phase;
2.One in late G2,provents entry
into mitosis;
P53,gene regulatory protein.DNA
damage activates p53 by an
indirect mechanism,
Mdm2 acts as a ubiquitin ligase
that targets p53 for destruction by
proteasomes,Phosphrylated p53
reduce its binding to Mdm2.
P21(CKI protein) binds to G1/S-
Cdk and S-Cdk and inhibits their
activities,thereby helping to block
entry into S phase.
?The summary of cell-cycle control system
Summary
An ordered sequence of cyclin-Cdk activities
triggers most of the events of the cell cycle,During
G1 phase,Cdk activity is reduced to a minimum by
Cdk inhibitors(CKIs),cyclin proteolysis,and
decreased cyclin gene transcription,When
environmental conditions are favorable,G1- and
G1/S-Cdks increase in concentration,overcoming
these inhibitory barriers in late G1 and triggering
the activation of S-Cdk,The S-Cdk phosphorylates
proteins at DNA replication origins,initiating DNA
synthesis through a mechanism that ensures that
the DNA is duplicated only once per cell cycle.
Once S-phase is completed,the activation of M-Cdk
leads to the events of early mitosis,whereby the cell
assembles a mitotic spindle and prepares for segregation
of the duplicated chromosomes---which consist of sister
chromatids glued together.
Ananphase is triggered by the destruction of the proteins
that hold the sisters together,The M-Cdk is then
inactivated by cyclin proteolysis,which leads to
cytokinesis and the end of M phase,Progression through
the cell cycle is regulated precisely by various inhibitory
mechanisms that arrest the cell cycle at specific
checkpoints when events are not completed successfully,
when DNA damage occurs,or when extracellular
conditions are unfavorable.
