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The Cell Cycle

By the end of the lecture, you will be able to:


Define cell cycle
Describe the phases of cell cycle
Identify the check points in cell cycle and
elaborate their significance.
Describe the role of cyclins other
molecules in the regulation of cell cycle.

Types of Cell Division


Prokaryotes as bacteria
Binary fission
Eukaryotes: mammal cells
Mitosis:
Growth, development & repair
Asexual reproduction (yields genetically identical cells)
Occurs in somatic (body) cells
Meiosis:
Sexual reproduction (yields genetically different cells
with half the No. of chromosomes)
Occurs in specific reproductive cells
Yields gametes (e.g., eggs & sperm)

Chromosome
duplication
(including DNA
synthesis)
Centromere

Sister
chromatids
Separation
of sister
chromatids

Sites of mitosis
In the foetus, babies and growing children mitosis occurs in
most tissues.

In adults, however, most tissues do not proliferate but mitosis


occurs regularly at the following sites:

Red bone marrow for production of blood cells


(erythropoiesis)
Lymphoid tissue - formation of lymphocytes (lymphooiesis)
Testes for spermatogenesis (production of spermatozoa)
Epidermis - replacement of superficial skin cells
Hair follicles - hair growth
Gastro-intestinal tract - renewal of epithelium

In adults mitosis does not normally occur in:


Neurons

Muscle cells

In the adult, many cells are normally quiescent but may be

stimulated to undergo mitosis. Such cells are said to be in G0


phase of the cell cycle.
Fibroblasts in connective tissue are normally quiescent but are

stimulated into the cell cycle following tissue injury.


Hepatocytes (liver cells) normally have a very slow rate of
turnover. The liver contains some cells with large tetraploid (4n)

nuclei (cells in G2) and binucleate cells (cells that have not yet
undergone cytokinesis).

The rate of cell division varies with the need for those
types of cells.
Cell type

Approximate life span

Skin cells

24 hour- 2 weeks

RBCs
hepatocytes
Intestinal lining cells

120 days
300-500 days
4-5 days

The Cell Cycle


Cell Cycle = Ordered sequence of events (M, G1, S and G2
phases) in the life of an eukaryotic cell, from division of a
parent cell into two daughter (progeny) cells
When mammalian cells are not inhibited and are
reproducing as rapidly as they can, this life cycle is as little
as 10-30 hours.
It is terminated by a series of events called mitosis that
cause division of the cell into two daughter cells
The actual stage of mitosis lasts only for 30 min---1 h. which
means that the cells spend more than 95% of its life cycle in
apparently (under light microscope) dormant state so
called the interval between mitosis called inter-phase

This mitosis=M phase include two visually events:


1. when the nucleus divides termed mitosis
2. when the cell physically splits in two termed cytokinesis
The long period between one M phase and next M phase (
average 23 hours This period is called: inter-phase
During inter-phase,
S phase (S = synthesis : DNA replication
Ensuring that when it does divide at the end of M phase each of
the newly created daughter cells will contain a full set of genes
After mitosis and before DNA synthesis begins, there is a gap
phase called G1: i.e between M and S phase
After DNA synthesis there is interval between the end of S
phase and the beginning of next M phase another gap called G2

Phases of the Cell Cycle


Cell cycle consists of:
Mitotic (M) phase
G1 phase (first gap)
S phase (synthesis)
G2 phase (second
gap)

Interphase

ATP is synthesized.
Damaged parts are repaired.
Wastes are excreted.
Proteins are made.
Organelles are formed.
Chromosomes are copied.
Specialized tasks are performed .

Mitosis

1. Prophase
Longest phase.
Chromatin coils.
Nucleus disappears.
Centrioles migrate.
Spindle forms.

1.
2.
3.
4.
5.
6.

Prophase
Prometaphase
metaphase
Anaphase
Telophase
Cytokinesis

Prometaphase

Metaphase

1. Breakdown of the nuclear envelope


2. Kinetochores become fully matured on the centromeres of the
chromosomes.
3. The mitotic spindles gain access to the mature kinetochores.
4. Sister chromatids are captured by microtubules
5. Once they have captured chromosomes, the kinetochore mictrotubles
begin to exert force on the chromosomes, moving them.

Anaphase

Centromere splits.
Chromatids are separated.
Chromatids are now called
chromosomes.

Telophase

Cytoplasm divides.
Nucleus reappears.
Chromosomes uncoil.

Cytokinesis
The cytoplasm divides and two identical
daughter cells are formed.

Cell cycle is regulated by a molecular control system


Sequential events of cell cycle are directed by control system similar to a
clock. Clock has specific checkpoints, where the cell cycle stops until a go a
head signal is received
For many cells, the G1 checkpoint seems to be the most important one

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

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?

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

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

M
Mitosis
G2
Gap 2

S
Synthesis

in G0, but can be called

G1
Gap 1

G0
Resting

back to cell cycle by


external cues
nerve & muscle cells
highly specialized
arrested in G0 & can
never divide

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?

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 :- activates cell signals

inactivated Cdk

Cell cycle controls


Cyclins regulatory proteins, its levels cycle in
the cell cycle
Cdks cyclin-dependent kinases

phosphorylates cellular proteins

activates proteins
Cdk-cyclin complex - triggers passage through
different stages of cell cycle

activated Cdk

Cdk
Degraded
cyclin

G2
checkpoint
Cyclin is
degraded
MPF

Cdk

Cyclin

Molecular mechanisms that help regulate the cell cycle

Spindle checkpoint

G2 / M checkpoint

Chromosomes attached at
metaphase plate

Replication completed
DNA integrity
Inactive

Active
Inactive

Cdk / G2
cyclin (MPF)

Active

APC

cytokinesis

mitosis

G2

G1

S
MPF = Mitosis
Promoting Factor
APC = Anaphase
Promoting Complex

Cdk / G1
cyclin
Active

G1 / S checkpoint

Inactive

Growth factors
Nutritional state of cell
Size of cell

External signals
Growth factors
coordination between cells
protein signals released by body cells that
stimulate other cells to divide
density-dependent inhibition
crowded cells stop dividing
each cell binds a bit of growth factor
not enough activator left to trigger division in
any one cell

anchorage dependence
to divide cells must be attached to a substrate
touch sensor receptors

Example of a Growth Factor


Platelet Derived Growth
Factor (PDGF)
made by platelets in blood
clots binding of PDGF to
cell receptors stimulates
cell division in fibroblast
(connective tissue) Wounds
healing
Other Extrinsic factors - interaction with other cells
Growth factors are necessary for stimulating cell proliferation . Some
growth factors act mainly, but not exclusively, on certain cells as indicated
by their names. e.g. Platelet derived growth factor (PDGF)
Epidermal growth factor (EGF)
Fibroblast growth factor (FGF)
Transforming growth factor (TGF)
Interleukin-2 (IL-2).

Growth Factors and Cancer

Growth factors can create cancers


Proto-oncogenes normal growth factor genes that:
Help to regulate the cell cycle
If switched ON can cause cancer
Example: RAS (rat sarcoma) activates
cyclins

Oncogenes

A gene that contributes to the production of a


cancer
Arise by mutation of proto-oncogenes
Interfering with the cell cycle control system
Cause tumours and uncontrolled cell proliferation

Tumor-suppressor genes Inhibits cell division

If switched OFF can cause cancer


Example: p53

Cancer & Cell Growth


Cancer is essentially a failure
of cell division control system or checkpoint
unrestrained, uncontrolled cell growth
What control is lost?
lose checkpoint stops
gene p53 plays a key role in G1/S restriction point
p53 protein halts cell division if it detects damaged DNA
Through :
stimulates repair enzymes to fix DNA
forces cell into G0 resting stage
keeps cell in G1 arrest
causes apoptosis of damaged cell
ALL cancers have to shut down p53 activity

Development of Cancer
Cancer develops only after a cell experiences ~6 key mutations hits)
1. Unlimited growth
Turn on growth promoter genes
2. Ignore checkpoints
Turn off tumor suppressor genes
(p53)
3. Escape apoptosis
Turn off suicide genes

4. Immortality = unlimited divisions


Turn on chromosome maintenance genes
5. Promotes blood vessel growth
Turn on blood vessel growth genes
6. Overcome anchor & density
dependence
Turn off touch-sensor gene

these hits caused by mutation, Mutations in cells can be triggered by


UV radiation
Cigarette smoke
Chemical exposure
Pollution
Radiation exposure
Age
Heat
Genetics

Clinical Applications
Chemotherapy of cancers:
Interrupting the cell cycle and preventing the cancer cells from
proliferating.
They are:
1. Cell cycle-specific (CCS): Act specifically on tumor cells
undergoing cycling)
i. Usually more active in a specific phase of the cell cycle.
ii. Particularly effective when large proportion of tumor
cells are proliferating.
OR
2. Cell cycle-non-specific (CCNS): Kill tumor cells in both
cycling and resting phases of the cell cycle.

Clinical Applications
Side effects:
The normal sites of cell proliferation are affected resulting in:
hair loss
intestinal disorders
anaemia
infertility