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Cell Cycle and Its Control
Mohammed Fathy Bayomy, MSc, MD
Lecturer
Clinical Oncology & Nuclear Medicine
Faculty of Medicine
Zagazig University
Cell Cycle
Series of events that take place in cell leading to its
division & duplication (replication)
Cell cycle can be divided in three periods: interphase—
during which cell grows, accumulating nutrients needed
for mitosis & duplicating its DNA & mitosis, during which
cell splits itself into two distinct cells, often called
"daughter cells" & final phase, cytokinesis, where new
cell is completely divided
Cell-division cycle is vital process by which zygote
develops into mature organism, as well as process by
which hair, skin, blood cells, & some internal organs are
renewed
Definition
Cell cycle consists of four distinct phases: G1 phase, S
phase (synthesis), G2 phase (collectively known as
interphase) & M phase (mitosis, cytokinesis)
M phase is itself composed of two tightly coupled
processes: mitosis, in which cell's chromosomes are
divided between two sister cells, & cytokinesis, in which
the cell's cytoplasm divides in half forming distinct cells.
Activation of each phase is dependent on proper
progression & completion of previous one. Cells that
have temporarily or reversibly stopped dividing are said
to have entered state of quiescence called G0 phase
Phases
• After cell division, each of the daughter cells begin
interphase of new cycle. Although various stages of
interphase are not usually morphologically
distinguishable, each phase of cell cycle has distinct
set of specialized biochemical processes that prepare
cell for initiation of cell division
4
Cell
division
Mitosis
3
DNA
repair
G2
1
Cell
grows,
doubles
in size
G1
S
2
Chromosome
duplication
G2/M checkpoint
G1/S
checkpoint
INTERPHASE
G1
G2
S
(DNA synthesis)
 Term "post-mitotic" is sometimes used to refer to both
quiescent & senescent cells
 Nonproliferative cells generally enter quiescent G0 state
from G1
 Some cells remain quiescent for long periods of time,
possibly indefinitely (as is often case for neurons). This
is very common for cells that are fully differentiated
 Some cells enter G0 phase semi-permanentally e.g.,
some liver & kidney cells
 Cellular senescence occurs in response to DNA damage
or degradation that would make cell's progeny nonviable;
it is often biochemical reaction; division of such cell
could, for example, become cancerous.
G0 Phase
Interphase
 Before cell can enter cell division, it needs to take in
nutrients. All of preparations are done during interphase
 Interphase is series of changes that takes place in newly
formed cell & its nucleus, before it becomes capable of
division again
 It is also called preparatory phase or intermitosis
 Previously it was called resting stage because there is
no apparent activity related to cell division
 Interphase proceeds in three stages, G1, S, G2
 Preceded by previous cycle of mitosis & cytokinesis
 The most significant event is replication of genetic
material (DNA) in S phase
G1 phase
 First phase within interphase, from end of previous M
phase until beginning of DNA synthesis, is called G1 (G
indicating gap)
 It is also called growth phase
 During this phase biosynthetic activities of cell, which
are considerably slowed down during M phase, resume
at high rate
 This phase is marked by use of 20 amino acids to form
millions of proteins & later on enzymes that are required
in S phase, mainly those needed for DNA replication.
 Duration of G1 is highly variable, even among different
cells of same species
 It is under control of p53 gene
S phase
 S phase starts when DNA replication occur
 When it is complete, all of chromosomes have been
replicated, i.e., each chromosome has two (sister)
chromatids
 During this phase, amount of DNA in cell has effectively
doubled, though ploidy of cell remains same.
 During this phase, synthesis is completed as quickly as
possible due to exposed base pairs being sensitive to
external factors such as any drugs taken or any
mutagens
G2 phase
 Gap between DNA synthesis and mitosis
 Cell will continue to grow
 G2 checkpoint control mechanism ensures that
everything is ready to enter M (mitosis) phase & divide
Interphase
 Before cell can enter cell division, it needs to take in
nutrients. All of preparations are done during interphase
 Interphase is series of changes that takes place in newly
formed cell & its nucleus, before it becomes capable of
division again
 It is also called preparatory phase or intermitosis
 Previously it was called resting stage because there is
no apparent activity related to cell division
 Interphase proceeds in three stages, G1, S, G2
 Preceded by previous cycle of mitosis & cytokinesis
 The most significant event is replication of genetic
material (DNA) in S phase
M phase
 Consists of karyokinesis & cytokinesis
 Mitosis is process by which cell separates chromosomes
in its cell nucleus into two identical sets in two nuclei:
during process of mitosis pairs of chromosomes
condense & attach to fibers that pull sister chromatids to
opposite sides of cell, followed immediately by
cytokinesis, which divides nuclei, cytoplasm, organelles
& cell membrane into two cells containing roughly equal
shares of these cellular components
 Mitosis & cytokinesis together define mitotic (M) phase
of cell cycle - division of mother cell into two daughter
cells, genetically identical to each other and to their
parent cell
 This accounts for approximately 10% of cell cycle
 Sequence of events is divided into phases
* Prophase
* Metaphase
* Anaphase
* Telophase
* Cytokinesis (part of M phase, not part of mitosis)
State Description Abbreviation
Quiescent/
Senescent
Gap 0 G0
Resting phase where cell has left cycle &
has stopped dividing
Interphase
Gap 1 G1
Cells increase in size in Gap 1. G1
checkpoint control mechanism ensures that
everything is ready for DNA synthesis
Synthesis S DNA replication occurs during this phase
Gap 2 G2
During gap between DNA synthesis &
mitosis, cell will continue to grow. G2
checkpoint control mechanism ensures that
everything is ready to enter M (mitosis)
phase & divide
Cell
division
Mitosis M
Cell growth stops at this stage & cellular
energy is focused on orderly division into
two daughter cells. checkpoint in middle of
mitosis (Metaphase Checkpoint) ensures
that cell is ready to complete cell division
Stages of Mitosis
Chromosomes
Chromosomal
DNA molecules
Centromere
Chromosome
arm
1
Chromosomes
Chromosomal
DNA molecules
Centromere
Chromosome
arm
Chromosome duplication
(including DNA replication)
and condensation
Sister
chromatids
1
2
Chromosomes
Chromosomal
DNA molecules
Centromere
Chromosome
arm
Chromosome duplication
(including DNA replication)
and condensation
Sister
chromatids
Separation of sister
chromatids into
two chromosomes
1
2
3
Cell Cycle Control
Synthesis
(transcription and translation)
Methods of cellular regulation
Major players
• Cyclins
• cdk (cyclin – dependent kinases)
• MPF (Maturation Promoting Factor) = cyclin B-
cdk1 kinase (“mitotic cdk”)
• CAK (Cdk Activating Kinases) regulators of
cdks
• CKI – cdk inhibitory subunits
• APC (Anaphase Promoting Complex)
• cdc34/SCF ubiquitination pathways which
activate proteolysis via proteosomes
* Definition: family of proteins that
activate cyclin-dependent kinase
(Cdk) enzymes
* Include: cyclin A, cyclin B, cyclin D,
cyclin E
Cyclins
* Definition: family of protein
kinases have role in regulating cell
cycle
* Include: cdk1, cdk2, cdk4, cdk6
Cyclin – dependent kinases
Cyclins
Cyclin dependent kinases (cdks)
Cdk1
Cyclin DG1
Cyclin E
Cyclin A
S
Cdk4,6
Cdk2
Cyclin A
Cyclin B
M
* Definition: heterodimeric protein composed of cyclin B &
cyclin-dependent kinase (CDK1)
* Function: promotes entrance into mitosis (M phase) from
G2 phase by phosphorylating multiple proteins needed
during mitosis
Maturation Promoting Factor
* Function: activates cyclin-CDK complex
by phosphorylation. CAK itself is member
of the Cdk family & functions as positive
regulator of Cdk1, Cdk2, Cdk4, Cdk6
Cdk Activating Kinases
* Definition: protein which inhibits cdK
* Two families
- cip/kip family: p21, p27 & p57
- INK4a/ARF family: p16INK4a, p19ARF
cdk inhibitory subunits
* Definition: E3 ubiquitin ligase that marks
target cell cycle proteins for degradation
by 26S proteasome
Anaphase Promoting Complex
APC
cdk1
Cyclin B
Fzr
Fzy
Anaphase
cdc14
Sister chromatid separation from prometaphase to anaphase
Securin
Separase
Cohesin
metaphase
Securin
Separase
Cohesin
prometaphase
APC
Check
point
Separase
APC
Separase
anaphase
Check
point
* Definition: Skp, Cullin, F-box containing complex
(or SCF complex) is a multi-protein E3 ubiquitin
ligase complex catalyzing ubiquitination of
proteins destined for proteasomal degradation. It
has important roles in ubiquitination of proteins
involved in cell cycle & also marks various other
cellular proteins for destruction
cdc34/SCF Pathway
G1 checkpoint
G1
G2
G2 checkpoint
M checkpoint
M
S
Control
system
G1 checkpoint
G1 G1
G0
(a) Cell receives go-ahead
signal
(b) Cell does not receive a
go-ahead signal
P
Cyc D
cdk4
pRB
E2F
E2FE2F
E2F P
PP
P
E2F
E2F
E2F
E2F
Cyc E
cdk2

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Cell cycle

  • 1. Cell Cycle and Its Control Mohammed Fathy Bayomy, MSc, MD Lecturer Clinical Oncology & Nuclear Medicine Faculty of Medicine Zagazig University
  • 3. Series of events that take place in cell leading to its division & duplication (replication) Cell cycle can be divided in three periods: interphase— during which cell grows, accumulating nutrients needed for mitosis & duplicating its DNA & mitosis, during which cell splits itself into two distinct cells, often called "daughter cells" & final phase, cytokinesis, where new cell is completely divided Cell-division cycle is vital process by which zygote develops into mature organism, as well as process by which hair, skin, blood cells, & some internal organs are renewed Definition
  • 4. Cell cycle consists of four distinct phases: G1 phase, S phase (synthesis), G2 phase (collectively known as interphase) & M phase (mitosis, cytokinesis) M phase is itself composed of two tightly coupled processes: mitosis, in which cell's chromosomes are divided between two sister cells, & cytokinesis, in which the cell's cytoplasm divides in half forming distinct cells. Activation of each phase is dependent on proper progression & completion of previous one. Cells that have temporarily or reversibly stopped dividing are said to have entered state of quiescence called G0 phase Phases
  • 5. • After cell division, each of the daughter cells begin interphase of new cycle. Although various stages of interphase are not usually morphologically distinguishable, each phase of cell cycle has distinct set of specialized biochemical processes that prepare cell for initiation of cell division
  • 8.  Term "post-mitotic" is sometimes used to refer to both quiescent & senescent cells  Nonproliferative cells generally enter quiescent G0 state from G1  Some cells remain quiescent for long periods of time, possibly indefinitely (as is often case for neurons). This is very common for cells that are fully differentiated  Some cells enter G0 phase semi-permanentally e.g., some liver & kidney cells  Cellular senescence occurs in response to DNA damage or degradation that would make cell's progeny nonviable; it is often biochemical reaction; division of such cell could, for example, become cancerous. G0 Phase
  • 9. Interphase  Before cell can enter cell division, it needs to take in nutrients. All of preparations are done during interphase  Interphase is series of changes that takes place in newly formed cell & its nucleus, before it becomes capable of division again  It is also called preparatory phase or intermitosis  Previously it was called resting stage because there is no apparent activity related to cell division  Interphase proceeds in three stages, G1, S, G2  Preceded by previous cycle of mitosis & cytokinesis  The most significant event is replication of genetic material (DNA) in S phase
  • 10. G1 phase  First phase within interphase, from end of previous M phase until beginning of DNA synthesis, is called G1 (G indicating gap)  It is also called growth phase  During this phase biosynthetic activities of cell, which are considerably slowed down during M phase, resume at high rate  This phase is marked by use of 20 amino acids to form millions of proteins & later on enzymes that are required in S phase, mainly those needed for DNA replication.  Duration of G1 is highly variable, even among different cells of same species  It is under control of p53 gene
  • 11. S phase  S phase starts when DNA replication occur  When it is complete, all of chromosomes have been replicated, i.e., each chromosome has two (sister) chromatids  During this phase, amount of DNA in cell has effectively doubled, though ploidy of cell remains same.  During this phase, synthesis is completed as quickly as possible due to exposed base pairs being sensitive to external factors such as any drugs taken or any mutagens
  • 12. G2 phase  Gap between DNA synthesis and mitosis  Cell will continue to grow  G2 checkpoint control mechanism ensures that everything is ready to enter M (mitosis) phase & divide
  • 13. Interphase  Before cell can enter cell division, it needs to take in nutrients. All of preparations are done during interphase  Interphase is series of changes that takes place in newly formed cell & its nucleus, before it becomes capable of division again  It is also called preparatory phase or intermitosis  Previously it was called resting stage because there is no apparent activity related to cell division  Interphase proceeds in three stages, G1, S, G2  Preceded by previous cycle of mitosis & cytokinesis  The most significant event is replication of genetic material (DNA) in S phase
  • 14. M phase  Consists of karyokinesis & cytokinesis  Mitosis is process by which cell separates chromosomes in its cell nucleus into two identical sets in two nuclei: during process of mitosis pairs of chromosomes condense & attach to fibers that pull sister chromatids to opposite sides of cell, followed immediately by cytokinesis, which divides nuclei, cytoplasm, organelles & cell membrane into two cells containing roughly equal shares of these cellular components
  • 15.  Mitosis & cytokinesis together define mitotic (M) phase of cell cycle - division of mother cell into two daughter cells, genetically identical to each other and to their parent cell  This accounts for approximately 10% of cell cycle  Sequence of events is divided into phases * Prophase * Metaphase * Anaphase * Telophase * Cytokinesis (part of M phase, not part of mitosis)
  • 16. State Description Abbreviation Quiescent/ Senescent Gap 0 G0 Resting phase where cell has left cycle & has stopped dividing Interphase Gap 1 G1 Cells increase in size in Gap 1. G1 checkpoint control mechanism ensures that everything is ready for DNA synthesis Synthesis S DNA replication occurs during this phase Gap 2 G2 During gap between DNA synthesis & mitosis, cell will continue to grow. G2 checkpoint control mechanism ensures that everything is ready to enter M (mitosis) phase & divide Cell division Mitosis M Cell growth stops at this stage & cellular energy is focused on orderly division into two daughter cells. checkpoint in middle of mitosis (Metaphase Checkpoint) ensures that cell is ready to complete cell division
  • 20. Chromosomes Chromosomal DNA molecules Centromere Chromosome arm Chromosome duplication (including DNA replication) and condensation Sister chromatids Separation of sister chromatids into two chromosomes 1 2 3
  • 23. Major players • Cyclins • cdk (cyclin – dependent kinases) • MPF (Maturation Promoting Factor) = cyclin B- cdk1 kinase (“mitotic cdk”) • CAK (Cdk Activating Kinases) regulators of cdks • CKI – cdk inhibitory subunits • APC (Anaphase Promoting Complex) • cdc34/SCF ubiquitination pathways which activate proteolysis via proteosomes
  • 24. * Definition: family of proteins that activate cyclin-dependent kinase (Cdk) enzymes * Include: cyclin A, cyclin B, cyclin D, cyclin E Cyclins
  • 25. * Definition: family of protein kinases have role in regulating cell cycle * Include: cdk1, cdk2, cdk4, cdk6 Cyclin – dependent kinases
  • 26. Cyclins Cyclin dependent kinases (cdks) Cdk1 Cyclin DG1 Cyclin E Cyclin A S Cdk4,6 Cdk2 Cyclin A Cyclin B M
  • 27. * Definition: heterodimeric protein composed of cyclin B & cyclin-dependent kinase (CDK1) * Function: promotes entrance into mitosis (M phase) from G2 phase by phosphorylating multiple proteins needed during mitosis Maturation Promoting Factor
  • 28. * Function: activates cyclin-CDK complex by phosphorylation. CAK itself is member of the Cdk family & functions as positive regulator of Cdk1, Cdk2, Cdk4, Cdk6 Cdk Activating Kinases
  • 29. * Definition: protein which inhibits cdK * Two families - cip/kip family: p21, p27 & p57 - INK4a/ARF family: p16INK4a, p19ARF cdk inhibitory subunits
  • 30.
  • 31. * Definition: E3 ubiquitin ligase that marks target cell cycle proteins for degradation by 26S proteasome Anaphase Promoting Complex
  • 33. Sister chromatid separation from prometaphase to anaphase Securin Separase Cohesin metaphase Securin Separase Cohesin prometaphase APC Check point Separase APC Separase anaphase Check point
  • 34. * Definition: Skp, Cullin, F-box containing complex (or SCF complex) is a multi-protein E3 ubiquitin ligase complex catalyzing ubiquitination of proteins destined for proteasomal degradation. It has important roles in ubiquitination of proteins involved in cell cycle & also marks various other cellular proteins for destruction cdc34/SCF Pathway
  • 35.
  • 36. G1 checkpoint G1 G2 G2 checkpoint M checkpoint M S Control system
  • 37. G1 checkpoint G1 G1 G0 (a) Cell receives go-ahead signal (b) Cell does not receive a go-ahead signal
  • 38.