Cell Cycle

Regulation of Cell cycle

Mitosis
(video)
Cellular Organization of the Genetic Material

• A cell’s endowment of DNA, its genetic

information
– Is called its genome

– In prokaryotes: the genome is often a single

long DNA molecule
– In eukaryotes: the genome consists of several
DNA molecules
– In human cells: they duplicate about 2 m of
DNA (250,000 x its diameter)
• The DNA molecules in a cell
– Are packaged into chromosomes

Figure 12.3
50 µm
Eukaryotic chromosomes www.geneticengineering.org/.../Graphics/Pack.gif

Consist of chromatin, a complex

of DNA and protein (Histones)
that condenses during cell
division

Each chromosome: contains one

long linear DNA molecule
carrying 100s to 1000s of
genes, the units that specify
genetic inheritance.

In animals

Somatic cells have two sets of

chromosomes

Gametes have one set of

chromosomes
Central Dogmas of molecular
biology
DNA RNA protein

DNA
DNA

Text, Fig. 16.5

Text, Fig. 16.11
Cellular dogma
• All organisms are made of cells
• All cells arise from other cells.

Exception:
• some fungi, embryos have no internal plasma
membranes
• viruses (true organisms???)
Two kinds of cells:
prokaryotes and eukaryotes

Text, Fig. 1.4

Prokaryote

Text, Fig. 7.4

Eukaryote:
animal example

Text, Fig. 7.4

• The Key Roles of Cell Division

• The continuity of life

– Is based upon the reproduction of cells, or cell
division
• Unicellular organisms
– Reproduce by cell division (binary fission)
100 µm

(a) Reproduction. An amoeba,

a single-celled eukaryote, is
dividing into two cells. Each
new cell will be an individual
Figure 12.2 A organism (LM).
• Multicellular organisms depend on cell division
for
– Development from a fertilized cell

– Growth

– Repair
200 µm 20 µm

(b) Growth and development. (c) Tissue renewal. These dividing

This micrograph shows a bone marrow cells (arrow) will
sand dollar embryo shortly give rise to new blood cells (LM).
after the fertilized egg divided,
Figure 12.2 B, C forming two cells (LM).
• Cell division results in genetically identical
daughter cells (Mitosis, somatic cells) or non
identical daughter cells (Meiosis, gametic
cells)
• In mitosis: cells duplicate their genetic material
– Before they divide, ensuring that each
daughter cell receives an exact copy of the
genetic material, DNA
Distribution of Chromosomes During Cell Division
• In preparation for cell division
– DNA is replicated and the chromatins
condense
– Each duplicated chromosome consists of two
sister chromatids which contain identical
copies of its DNA.
 The two sister chromatids, which separate during
cell division 0.5 µm
A eukaryotic cell has multiple
chromosomes, one of which is
represented here. Before
duplication, each chromosome
Chromosome
has a single DNA molecule. duplication
(including DNA
synthesis)
Once duplicated, a chromosome
consists of two sister chromatids Centromere
connected at the centromere. Each
chromatid contains a copy of the
DNA molecule.

Sister
Separation chromatids
of sister
Mechanical processes separate chromatids
the sister chromatids into two
chromosomes and distribute
them to two daughter cells.
Figure 12.4 Centromeres Sister chromatids
Nucleus Chromatine Chromosome
Nucleolus condensing

Telophase.
1 Prophase. 2 Prometaphase. 3 Metaphase. 4 Anaphase. The 5
The chromatin We now see discrete chromatids of each Daughter
is condensing. chromosomes; each The spindle is complete, chromosome have nuclei are forming.
The nucleolus is consists of two and the chromosomes, separated, and the Meanwhile, cytokinesis
beginning to identical sister attached to microtubules daughter chromosomes has started: The cell
disappear. chromatids. Later at their kinetochores, are moving to the ends plate, which will
Although not in prometaphase, the are all at the metaphase of cell as their divided the cytoplasm
yet visible nuclear envelop will plate. kinetochore in two, is growing
in the micrograph, fragment. microtubles shorten. toward the perimeter
the mitotic spindle is of the parent cell.
staring to from.
Figure 12.10
Mitotic cell cycle
• The mitotic phase alternates with interphase
(90% of the cell cycle) in the cell cycle
• A labeled probe can reveal patterns of gene
expression in different kinds of cells
• Mitosis:

videos
The Mitotic Spindle: A Closer Look
• The mitotic spindle
– Is an apparatus of microtubules (tubulin fibers-
a protein) and associated proteins that controls
chromosome movement during mitosis

• The spindle (spindle microtubules and asters)

arises from the centrosomes or microtubule-
organizing center
– In animal cells only, there are a pair of
centrioles
– In interphase, centrosome duplicates
• Some spindle microtubules (kinetochore microtubules)
– Attach to the kinetochores (at centromere) of
chromosomes and move the chromosomes to the
metaphase plate (by a tug-of-war)
Aster Centrosome

Sister Metaphase
chromatids Plate
Kinetochores

Overlapping
nonkinetochore
microtubules
Kinetochores
microtubules 0.5 µm
Chromosomes
Microtubules

Centrosome
Figure 12.7
1 µm
• Non Kinetochore microtubules from opposite
poles overlap and interact with each other.
• By metaphase, the microtubules of the aster
have grown and are in contact with the plasma
membrane.
• The spindle is then complete.
• In anaphase, sister chromatids separate
– And move along the kinetochore microtubules
toward opposite ends of the cell
– Nonkinetechore microtubules from opposite
poles overlap and push against each other,
elongating the cell by adding new tubulin
monomers to their overlapping ends, allowing
continued overlap.

• In telophase
– Genetically identical daughter nuclei form at
opposite ends of the cell
• In animal cells cytokinesis occurs by a process known as cleavage,
forming a cleavage furrow. The contractile ring: Actin microfilaments
associated with molecules of the motor protein myosin on the
cytoplmasmic side of the cleavage furrow.
• In plant cells, the vesicles derived from the Golgi apparatus produce a
cell plate at the middle of the cell
Binary Fission
• Prokaryotes (Bacteria)
– Reproduce by a type of cell division called
binary fission
• In binary fission
– The bacterial chromosome (a circular type)
replicates starting at the Origin of replication
site, producing two origins.
– The cell enlongates
– The two daughter chromosomes actively move
apart
1
Chromosome replication begins. Origin of
Cell wall
Soon thereafter, one copy of the replication
Plasma
origin moves rapidly toward the Membrane
other end of the cell. E. coli cell Bacterial
Two copies of origin Chromosome
2 Replication continues. One copy of
the origin is now at each end of
the cell.
Origin Origin
3 Replication finishes. The plasma
membrane grows inward, and
new cell wall is deposited.

4 Two daughter cells result.

Figure 12.11
Regulation of cell cycle
What stimulates cell division?
• The timing and rates of cell division in
different parts of animal and plants are crucial
for normal growth, development and
maintenance.
• The cell cycle is regulated by a molecular
control system
• The frequency of cell division
– Varies with the type of cell (skin vs liver vs
mature muscle and nerve cells)
• These cell cycle differences
– Result from regulation at the molecular level
The Cell Cycle Control System
• The sequential events of the cell cycle
– Are directed by a distinct cell cycle control
system, which is similar to a clock
– Has a built in clock,
– It is regulated by external adjustments and
– By internal controls
There are three checkpoints in the cell cycle that are
critical control points where stops and go-ahead
signals regulate the cycle
G1 checkpoint

Control
system S

G1

G2
M

M checkpoint
Figure 12.14 G2 checkpoint
• Of the three specific checkpoints, the G1 checkpoint, the
restriction point in mammalian cells, is the most important.
– Where the cell cycle stops until a go-ahead signal is
received

G0

G1 checkpoint

G1 G1

(a) If a cell receives a go-ahead signal at

(b) If a cell does not receive a go-ahead
the G1 checkpoint, the cell continues
signal at the G1checkpoint, the cell
Figure 12.15 A, B on in the cell cycle.
exits the cell cycle and goes into G0, a
nondividing state.
 Evidence for Cytoplasmic Signals
• Molecular signals present in the cytoplasm
– Regulate progress through the cell cycle
In each experiment, cultured mammalian cells at two different phases
EXPERIMENTS
of the cell cycle were induced to fuse.

Experiment 1 Experiment 2

S G1 M G1

RESULTS

S S M M

When a cell in the S phase was fused with a cell When a cell in the M phase was fused with a
in G1, the G1 cell immediately entered the S cell in G1, the G1 cell immediately began
phase—DNA was synthesized. mitosis— a spindle formed and chromatin
condensed, even though the chromosome had
not been duplicated.

CONCLUSION The results of fusing cells at two different phases of the cell cycle suggest
that molecules present in the cytoplasm of cells in the S or M phase control
Figure 12.13 A, B
the progression of phases.
The Cell Cycle Clock: Cyclins and
Cyclin-Dependent Kinases
• Two types of regulatory proteins are involved in
cell cycle control
• Cyclins and cyclin-dependent kinases (Cdks)

• Protein kinases activate or deactivate other

proteins by phosphorylating them. They are
present in constant amounts
• Cyclins fluctuate cyclically.
• The activity of cyclins and Cdks
– Fluctuates during the cell cycle
• i.e. MPF or maturation promotion factor or M-
phase-promoting factors trigger the cell´s
passage past the G2 checkpoint to the M
phase.
– MPF promotes mitosis by
• phosphorilating a variety of other protein
kinases
• Stimulating fragmentation of nuclear envelope
by phosphorilating various proteins in nuclear
lamina
• Triggering break down of cyclin thus
inactivating MPF.
 M G 1 S G2 M G1 S G 2 M
a) Fluctuation of MPF MPF activity
activity and cyclin
concentration during Cyclin
the cell cycle

Time
(b) Molecular mechanisms that
help regulate the cell cycle
Synthesis of cyclin
1 begins in late S phase and
continues through G2.
5
Because cyclin is protected
During G1, conditions in from degradation during this
the cell favor degradation stage, it accumulates.
of cyclin, and the Cdk

1
G

S
component of MPF is Cdk
recycled. Accumulated cyclin molecules
M
Degraded

2
G
Cyclin G2 combine with recycled Cdk
Cdk 2 molecules, producing enough
4 checkpoint
Cyclin is molecules of MPF to pass the
degraded
MPF Cyclin G2 checkpoint and initiate the
During anaphase, the cyclin events of mitosis.
component of MPF is degraded,
terminating the M phase. The cell
3 MPF promotes mitosis by phosphorylating
enters the G1 phase. various proteins. MPF‘s activity peaks during
metaphase.
Stop and Go Signs: Internal and External Signals at
the Checkpoints
• Both internal and external signals
– Control the cell cycle checkpoints

– Ie: the M phase checkpoint ensures that all

chromosomes are properly attached to the
spindle ant metaphase plate before anaphase,
thus insuring no gain or loss of chromosomes.
– The. Anaphase-promoting complex (APC) is
responsible for this . When all kinetochores
are attached, the APC promotes breakdown of
cyclin and inactivation of proteins holding sister
chromatids together.
• A variety of external chemical and physical
factors can influence cell division:
– Lack of escencial nutrients

– Absence of growth factors -or proteins

released by one group of cells that stimulate
others to divide.
• Each cell type probably responds specifically to
a certain growth factor or combination of
factors.
• At least 50 different growth factors can trigger
specific cells to divide.
• Cell division is affected by density-dependent
inhibition and anchorage dependence
• Cancer cells
– Exhibit neither density-dependent inhibition nor
anchorage dependence

25 µm

Cancer cells. Cancer cells usually

continue to divide well beyond a
single layer, forming a clump of
Figure 12.18 B overlapping cells.
Loss of Cell Cycle Controls in Cancer Cells
• Cancer cells
– Do not respond normally to the body’s control mechanisms,
they divide excessively and invade other tissues because
they are free of the body´s control mechanism.
– I.e.: Falure in proteins such as P53 (more than 50% of all
cancers- involved in M stage) and ras (30% of cancers-
involved in G stages) proteins promotes cancer
– Form tumors – they do not stop dividing when growth
factors are depleted because:
• Manufacture their own growth factors
• Have abnormality in the signaling pathway
• Have abnormal cell cycle control system.
– If and when they stop dividing, at random points, not at
normal checkpoints in cell cycle.
• Cancer cells can divide indefinatelly if have
continual supply of nutrients
• Normal cells die after 20-50 cell divisions under
culture conditions
• Cancer cells begin when a single cell in a
tissue undergoes TRANSFORMATION that
converts it from normal to cancer cell.
• If abnormal cells remain at originating site:
benign tumor,
• If cells are invasive that impare the function of
one or more organs: malignant tumor.
• Cancer cells:
– Unusual number of chromosomes

– Metabolic abnormalities

– Lose attachment to nearby cells, are carried by

blood and lymph systems to other tissues,
forming metastasis
– May secrete signal molecules that cause blood
vessels to grow toward the tumor.

cancer video….
• The following slides are replaced by activities
and videos from the CD
Phases of the Cell Cycle
• The cell cycle may last 24 hr. and consists of
– The mitotic phase 10-12 hrs

– Interphase
INTERPHASE

S
G1 (DNA synthesis)

s
s si
s i ne
G2
ito ki
M yto
C

MI
(M TOT
) P IC
HA
SE

Figure 12.5
• Interphase:cell grows by producing proteins
and cytoplasmic organelles.
• can be divided into subphases
– G1 phase (first gap)

– S phase (synthesis) Chromosome replicated

– G2 phase (second gap)

• The mitotic phase
– Is made up of mitosis and cytokinesis
• Mitosis consists of five distinct phases
– Prophase

– Prometaphase

– Metaphase

– Anaphase

– Telophase
 G2 OF
PROPHASE PROMETAPHASE
INTERPHASE Aster
Centrosomes Fragments Kinetochore
Early mitotic
(with centriole pairs) Chromatin Centromere of nuclear
(duplicated) spindle envelope
Nonkinetochore
microtubules

Nucleolus Nuclear Plasma Chromosome, consisting Kinetochore

envelope membrane of two sister chromatids microtubule
 METAPHASE ANAPHASE TELOPHASE AND CYTOKINESIS

Metaphase
plate Cleavage Nucleolus
furrow forming

Nuclear
envelope
Spindle Centrosome at Daughter forming
6 one spindle pole chromosomes
 Genetics – self replication
DNA cells organisms

Text, Fig. 16.7 Text CD Text, Fig. 13.2