The

Cell Cycle

The Cell Cycle

KEY CONCEPT
Cells have dis2nct phases of growth, reproduc2on, and
normal func2ons.

What is cell cycle?

Cell cycle is dened as a period from
the end of one division to the
beginning of next division of a
prolifera<ve cell.

The Cell Cycle

Your body cells go through a cycle too. This cycle allows
new cells to be created to heal or replace dead or
damaged cells.

Cell division <ming

Dierent cells have cell cycles of dierent
lengths;
Cell type Cell cycle <me
Nerve Cells
Human Liver Cells
Red blood cell
Skin cell
Intes<nal epithelial cells
Yeast cells
Bacteria

never
1 year
4 months
2 weeks
12 hours
1.5 to 3 hours
90 minutes

Some cells are unlikely to divide (G0).

The cell cycle

The cell cycle for prokaryo<c
cells is a quick succession of
growth, DNA replica<on, and
cell division. Cell division in
prokaryotes is a one-step
process called binary ssion
(shown right).
Eukaryo<c cells have a more
complex cell cycle than
prokaryo<c cells.

How is the eukaryo<c

cell cycle divided?
The <me between cell divisions
is called interphase. The length
of interphase varies depending
on cell type.
Eukaryo<c interphase is divided
into three steps, or phases: G1, S,
and G2.

Eukaryo<c cells divide during the
M phase of the cell cycle. The M
phase consists of two steps:
mitosis and cytokinesis.

Interphase
The stage between two
successive cell divisions
(the holding stage).
Some 90 % of a cell's
<me in the normal cell
cycle may be spent in
this phase
C = chroma<n
I = nucleolus

Parts of Interphase
G1 Phase
Growing
Synthesize new proteins and
organelles
Doing their jobs
Longest phase of cell cycle
S Phase
Chromosomes(DNA) are
replicated
Key proteins associated with
replica<on are made
(centromeres)
G2 Phase
Shortest of the 3 phases of
interphase
Organelles and molecules for cell
division are produced (centrioles)
Check-up phase before mitosis

What happens during the M phase

of the eukaryo<c cell cycle?
The M phase is usually much
shorter than interphase and
results in two daughter cells.

The rst step of the M phase is
mitosis. The cells nucleus
divides during mitosis.
The second step of the M phase
is cytokinesis, during which the
cells cytoplasm is divided.

What are the steps of mitosis?

Mitosis consists of four steps:
Prophase
Metaphase
Anaphase
Telophase

Cytokinesis
Cytoplasmic
division and other
changes exclusive of
nuclear division that
are a part of mitosis
or meiosis.
-

Regulation of the Cell Cycle

The Cell Cycle Control System

The sequen<al events of the cell cycle are directed
by a dis<nct cell cycle control system, which is
similar to a clock

The clock has specic checkpoints where the cell
cycle stops un<l a go-ahead signal is received

Deni<on of Checkpoint
n

Cell cycle is a highly ordered process: the

ini<a<on of later event depends on the
comple<on of earlier events.
The control mechanisms that enforce this
ordered dependency are called cell cycle
checkpoint.

G1 checkpoint

Control
system

G1

M checkpoint
G2 checkpoint

G2

Control of the Cell Cycle

The cell cycle is controlled at three checkpoints:
1. G1/S checkpoint
-the cell decides to divide

2. G2/M checkpoint
-the cell makes a commitment to mitosis
3. late metaphase (spindle) checkpoint
-the cell ensures that all chromosomes are
ahached to the spindle
24

Regula<on of the Cell Cycle:

Cell Cycle Checkpoints

E.g. Oocytes

can sister chroma<ds separate correctly?

has DNA synthesis been completed

correctly?
commitment to mitosis

can DNA synthesis begin?

Differentiating cells

 For many cells, the G1 checkpoint seems to be

the most important one
If a cell receives a go-ahead signal at the G1
checkpoint, it will usually complete the S, G2,
and M phases and divide
If the cell does not receive the go-ahead signal,
it will exit the cycle, switching into a nondividing
state called the G0 phase

LE 12-15

G0
G1 checkpoint

G1
If a cell receives a go-ahead
signal at the G1 checkpoint, the
cell con2nues on in the cell
cycle.

G1
If a cell does not receive a go-
ahead signal at the G1
checkpoint, the cell exits the cell
cycle and goes into G0, a
nondividing state.

Examples of checkpoints in the cell cycle

Stop and Go Signs: Internal and External

Signals at the Checkpoints
An example of an internal signal is that
kinetochores not ahached to spindle microtubules
send a molecular signal that delays anaphase
Some external signals are growth factors, proteins
released by certain cells that s<mulate other cells
to divide
For example, platelet-derived growth factor (PDGF)
s<mulates the division of human broblast cells in
culture

How do cells know when to divide and

when not to?
Internal regulators are proteins that respond
to events inside the cell.
Some proteins make sure cells do not enter
mitosis un<l all of the chromosomes have been
replicated.

Two types of regulatory proteins are involved in

cell cycle control: cyclins and cyclin-dependent
kinases (Cdks)
The ac<vity of cyclins and Cdks uctuates during
the cell cycle

LE 12-14
Proteins
within the cell control the cell cycle
Signals affecting critical checkpoints determine whether
the cell will divide (cyclins, kinases)

G1 checkpoint

G1

S
Control
system
M

M checkpoint
G2 checkpoint

G2

Control of the Cell Cycle

At G1/S checkpoint:
- G1 cyclins accumulate
- G1 cyclins bind with Cdc2 to create the ac<ve
G1/S Cdk
- G1/S Cdk phosphorylates a number of
molecules that ul<mately increase the
enzymes required for DNA replica<on

32

LE 12-16b

Degraded
cyclin
Cyclin is
degraded

G2
checkpoint

MPF

Cdk

in accumula2on
Cycl

Cdk

Cyclin

Molecular mechanisms that help regulate the cell cycle

Rela2ve concentra2on

LE 12-16a

G1

G2

G1 S

G2

MPF ac2vity
Cyclin

Time
Fluctua2on of MPF ac2vity and cyclin concentra2on
during the cell cycle

External Factors that can Influence

Cell Division

1. Chemical factors-

a. Lack of nutrients inhibit cell

division
b. Presence of specific growth
factors are needed for cell division
Platelet-derived Growth Factor
(PDGF) is required for division of
fibroblasts used in healing
Receptors on plasma membrane
bind PDGF and trigger pathway to
signal cell division

2. Physical factors-

a. Density-dependent inhibition

Cell division limited by quantities of

nutrients and growth regulators

b. Anchorage-dependent inhibition
Cells must attach to substratum
(surface)
Anchorage is signaled to cell-cycle
control system by linkage between
membrane proteins and elements of
cytoskeleton

External Regulators
External regulators - Proteins that respond to events
outside the cell are called external regulators.
External regulators direct cells to speed up or slow
down the cell cycle.
Growth factors are among the most important
external regulators, which tell cells to speed up
division. When is this important?
Molecules found on the surfaces of neighboring cells
omen have an opposite eect, causing cells to slow
down or stop their cell cycles.

External Signals

1. Growth factors stimulate cell division

Density-dependent inhibition of cell division

Cells anchor to dish surface and

divide (anchorage dependence).
When cells have formed a complete
single layer, they stop dividing
(density-dependent inhibi2on).

If some cells are scraped away, the

remaining cells divide to ll the gap and
then stop (density-dependent inhibi2on).

Normal mammalian cells

25 m

 Mitosis occurs only if:

the cell is large enough
and the DNA is undamaged
If the DNA is damaged, the cell
commits suicide so it doesnt
pass on bad DNA

How DNA
damage
arrests the
cell cycle?

Control of Cell Cycle

What happens when checkpoints fail?
Cancer can occur
Cancer is the uncontrolled growth of cells.

Cancer Cells have Escaped Cell-cycle

Control
Cancer cells do not respond normally to the
bodys control mechanisms and divide
excessively
1. Density-independentmake their own
growth factors and continue to divide
uncontrolled (immortal)
2. Anchorage-independent

LE 12-18a

Cells anchor to dish surface and

divide (anchorage dependence).

When cells have formed a complete

single layer, they stop dividing
(density-dependent inhibi2on).

If some cells are scraped away, the

remaining cells divide to ll the gap and
then stop (density-dependent inhibi2on).

Normal mammalian cells

25 m

LE 12-18b

Cancer cells do not exhibit

anchorage dependence
or density-dependent inhibi2on.

25 m
Cancer cells

Loss of Cell Cycle Controls in Cancer Cells

Cancer cells do not respond normally to the
bodys control mechanisms
Cancer cells form tumors, masses of abnormal
cells within otherwise normal <ssue
If abnormal cells remain at the original site, the
lump is called a benign tumor
Malignant tumors invade surrounding <ssues
and can metastasize, expor<ng cancer cells to
other parts of the body, where they may form
secondary tumors

Abnormal cells that escape cell-cycle control are

products of mutated or transformed normal
cells

1. May proliferate to form a tumoran unregulated

growing mass of cells within normal tissue
Benign tumorif cells remain at the original site
Malignant tumorif mass impairs normal
function of one or more organs of the body
Excessive proliferation
Cells with unusual number of chromosomes
Aberrant metabolism
Detaches and migrates through body
(metastasis)

Growth control in a normal cell

Signaling cell

Growth factor =
Growth factor binds to receptor
Receptor sets off
a signal
cascade to
nucleus

target cell

Nucleus

target cell enters

S-phase and
divides,
eventually
repairing
wound

Several ways to get faulty growth control in a cancer cell

2. Mutant receptor might
turn on even without
binding growth factor

1. Cell might
produce
its own
growth
factor

3. Signal cascade
might occur even
without trigger
from receptor

Breast cancer cell

Mammogram: normal (left) and cancerous (right)

What causes Cancer?

Cancer is caused by
alterations or mutations in
the genetic code
Can be induced in somatic
cells by:

Carcinogenic
chemicals
Radiation
Some viruses
Heredity - 5%
53

 What is the molecular basis of cancer?

Cancer is a gene<c disease.
Muta<ons in genes result in altered proteins
During cell division
External agents
Random event
Most cancers result from muta<ons in soma<c
cells
Some cancers are caused by muta<ons in
germline cells

55

What are the genes responsible for tumorigenic

cell growth?
Normal
Proto-oncogenes

Tumor suppressor genes

Cell growth
and
proliferation

Cancer
Mutated or activated
oncogenes
Loss or mutation of
Tumor suppressor genes

++

Malignant
transformation

56

The Cell Cycle and Cancer

Characteristics of Cancer Cells
Cancer cells lack differentiation.
Cancer cells have abnormal nuclei.
Cancer cells form tumors.
Cancer cells undergo metastasis and
angiogenesis.

Cancer cells lack differentiation

Unlike normal cells that differentiate into
muscle or nerves cells, cancer cells have an
abnormal form and are nonspecialized.

Normal cells enter the cell cycle only about
50 times; cancer cells are immortal in that they
can enter the cell cycle repeatedly.

Cancer cells have abnormal nuclei

The nuclei may be enlarged and may have an
abnormal number of chromosomes.

The chromosomes have mutated; some chromosomes
may be duplicated or deleted.

Gene amplification, extra copies of genes, is more
frequent in cancerous cells.

Whereas ordinary cells with DNA damage undergo
apoptosis, cancer cells do not.

Cancer cells form tumors

Normal cells are anchored and stop dividing
when in contact with other cells; i.e., they
exhibit contact inhibition.

Cancer cells invade and destroy normal
tissue and their growth is not inhibited.

Cancer cells pile on top of each other to
form a tumor.

Cancer cells undergo metastasis and angiogenesis

A benign tumor is encapsulated and does not invade adjacent
tissue.

Cancer in situ is a tumor in its place of origin but is not
encapsulatedit will invade surrounding tissues.

Many types of cancer can undergo metastasis, in which new
tumors form which are distant from the primary tumor.

Angiogenesis, the formation of new blood vessels, is required
to bring nutrients and oxygen to the tumor.

A cancer patients prognosis depends on whether the tumor
has invaded surrounding tissue, whether there is lymph node
involvement, and whether there are metastatic tumors
elsewhere in the body.

LE 12-19

Lymph
vessel

Tumor

Blood
vessel

Glandular
2ssue
Cancer cell
A tumor grows from a
single cancer cell.

Cancer cells invade

neighboring 2ssue.

Cancer cells spread

through lymph and
blood vessels to
other parts of the
body.

Metasta2c
tumor
A small percentage
of cancer cells may
survive and establish
a new tumor in another
part of the body.

Cancer treatment:
Attack Actively Dividing Cells

Three treatments for cancer:

1. Surgery
2. Radiation
3. Phase-specific chemotherapies

Phase-specific Chemotherapies
1. Prevent cells from entering the S-phase

2. Block the S phase

3. Block or stop mitosis

Phase Specicity of Cytotoxic Drugs

Phase of cell cyle

Effective agents

G1

Steroids, asparaginase

S phase

Antimetabolites

G2

Bleomycin, etoposide

Mitosis

Vinca alkaloids, taxanes

Phase non-specific

Alkylating agents,
nitrosoureas, antibiotics,
procarbazine, dacarbazine,
platinums

But chemotherapy cant discriminate between

cancer cells and normal cells.
May affect all rapidly dividing cells
Which cells divide rapidly?

So.... what would be the side effects?

Chemotherapy Side Eects

Chemotherapy targets cells which are dividing
rapidly.
Chemotherapy cannot dis<nguish between
normal cells and cancer cells
Healthy Cells which have a high rate of growth
and mul<plica<on include cells of the bone
marrow, hair, GI mucosa and skin.

The End