Cell Cycle, cell division and death

Pramod SN
Davangere University
 Control of cell growth
• Cells in a multicellular organism communicate
through chemical signals
• Cells are stimulated when extra cellular signalling
molecules bind to a receptor
• Each receptor recognises a specific protein (ligand)
• Receptors act as transducers that convert the signal
from one physical form to another.
 The cell cycle
• The eukaryotic cell cycle consists of
distinct phases
• The most dramatic events are nuclear
division (mitosis) and cytoplasmic
division (cytokinesis)
• This is the M phase
• The rest of the cell cycle is called
interphase which is, deceptively,
uneventful
• During interphase the cell replicates its
DNA, transcribes genes, synthesises
proteins and grows in mass
 Phases of the cell cycle

• S phase – DNA replicates

• M phase – nucleus divides
(mitosis) and cytoplasm
divides (cytokinesis)
• G1 phase – gap between M
and S phase
• G2 phase – between S and M
phase
CELL CYCLE CHARACTERS
 Cell cycle control
• Cell cycle machinery is subordinate to a cell cycle control
system
• The control system consists mainly of protein complexes
• These complexes consist of a cyclin subunit and a Cdk
subunit
• The cyclin has regulatory function, the Cdk catalytic
function
• Cdk expression is constant, but cyclin concentrations rise
and fall at specific times in the cell cycle
• The Cdks are cyclically activated by cyclin binding and by
phosphorylation status
• Once activated, Cdks phosphorylate key proteins in the
cell
• Different cyclin-Cdk complexes trigger different cell
cycle steps
• Some drive the cell into M phase, others into S phase
• The cell cycle control system has in-built molecular
breaks (checkpoints)
• The checkpoints ensure that the next step does not
begin until the previous one is complete
 MPF – G2 phase promoter
MPF (“maturation-promoting 
factor” or “M-phase-promoting-
factor”)

It triggers the cell’s passage past the

G2 checkpoint to the M
phase.

MPF promotes mitosis by

phosphorylating a variety of other
protein kinases.

MPF stimulates
fragmentation of
the nuclear envelope.
Three checkpoints:
The G1/S cell cycle checkpoint
G2/M DNA damage checkpoint
Mitosis checkpoint

G1/S cell cycle checkpoint

controls the passage of eukaryotic cells from the first 'gap'
phase (G1) into the DNA synthesis phase (S).

Checks:
That the size is CORRECT
That the environment is CORRECT
 G1/S cell cycle checkpoint
How do they do that?
Major proteins involved:
Cyclins (proteins) - level fluctuate in the cell cycle.
&
Cyclin dependent KINASES* (Cdks)
They add phosphate groups to proteins that control processes in
the cell cycle.
They only do this when the cyclins are present.
 The G1 checkpoint
• This checkpoint is
influenced by the action
of cyclin-dependant
kinase inhibitors (CKIs,
e.g. p21, p16)
• E.g. p53 senses DNA
damage and induces p21
expression
• CKIs inactivate cyclin-Cdk
complexes
 G2/M DNA damage checkpoint
The G2/M DNA damage checkpoint prevents the cell from
entering mitosis (M phase) if the genome is damaged.
It also checks if the cell is big enough (i.e. has the resources to
undergo mitosis)
Almost exclusively, internally controlled

M checkpoint
The M checkpoint is where the attachment of the spindle
fibres to the centromeres is assessed.
Only if this is correct can mitosis proceed.
Failure to attach spindle fibres correctly would lead to failure to
separate chromosomes
In conclusion, the cell is faced with a number of points in the cell cycle
where it has to satisfy certain molecular requirements before it is
permitted to continue along the cell cycle.

18_17_arrest_checkpt.jpg
 Cellular adaptations of growth and
differentiation
• Cells must respond to a variety of stimuli
that may be hormonal, paracrine or
through direct cell contact
• These stimuli may arise under physiological
or pathological conditions
• The way that cells adapt in terms of growth
and differentiation depends in part on their
ability to divide
CELL GENESIS or CELL DIVISIONS
MITOSIS and MEOSIS
 Cellular proliferative capacity
• Tissues can be classified according to the ability of
their cells to divide
• Some tissues contain a pool of cells that move rapidly
from one cell cycle to the next. These are labile cells
• Some cells dismantle their cell cycle control machinery
and exit the cell cycle
• These cells are said to be in G0.
• Some of these cells can re-enter the cell cycle when
stimulated, e.g. by growth factors. These are stable cells
• Others are unable to re-enter the cell cycle. These are
permanent cells
 Introduction

• The continuity of life from one cell to another is

based on the reproduction of cells via cell division.

• This division process occurs as part of the cell cycle

(the life of a cell from its origin in the division of a
parent cell until its own division into two).

• The division of a unicellullar organism (e.g. Amoeba)

reproduces an entire organism, increasing the
population.

• Cell division is also central to the development of a

multicellular organism that begins as a fertilized egg
or zygote.
 Multicellular organisms also use cell division to repair and renew cells that
die normally or by accidents (blood cells from bone marrow).

Cell division distributes the genetic

material (DNA) to two daughter cells.

Division is differ among cells:.

- Skin cells divide frequently.

- Liver cells divide when needed (damage repair).
- Nerve cells do not divide at all.
 Cell division distributes identical sets of chromosomes to daughter cells

• A cell’s genetic information genome packaged as DNA.

• In prokaryotes, the genome is often a single long DNA molecule.
– In eukaryotes, the genome consists of several DNA molecules.
• A human cell must duplicate about 3 m of DNA and separate the two copies
such that each daughter cell ends up with a complete genome.
• DNA molecules are packaged into chromosomes.
– Every eukaryotic species has a characteristic number of chromosomes in the nucleus.
– Human somatic cells (body cells) have
46 chromosomes.
– Human gametes (sperm or eggs) have
23 chromosomes, half the number in
a somatic cell .

• Each eukaryotic chromosome consists of a long, linear DNA molecule.

• Each chromosome has hundreds or thousands of genes (the units that specify an
organism’s inherited characters
• This DNA-protein complex (chromatin) is organized into a long thin fiber.
• After the DNA duplication, chromatin condenses form
(chromosome).

• Each duplicated chromosome consists of two

sister chromatids which contain identical
copies of the chromosome’s DNA.
• The narrow region where the chromosomal
strands connect is the called centromere.
• Later, the sister chromatids are pulled apart
and repackaged into two new nuclei at
opposite ends of the parent cell during cell
division.
• The process of the formation of the two
daughter nuclei called (mitosis) and is usually
followed by division of the cytoplasm
(cytokinesis). It occurs in somatic cells .
 Chromatid
Chromatin +
DNA
Sister chromatid

Homologous
Chromosome
Centromere

Chromosome
• In the gonads , cells undergo a meiosis division, which yields four daughter
cells, each with half the chromosomes number of the parent cell.
– In humans, meiosis reduces the number of chromosomes from 46 to 23.

• Each of us inherited 23 chromosomes from each parent: one set in an egg and
one set in a sperm during meiosis.

• gametes (eggs or sperm) are produced only in gonads (ovaries or testes).

• The fertilized egg undergoes trillions of cycles of mitosis and cytokinesis to

produce a fully developed multicellular human.

• These processes continue every day to replace dead and damaged cell.

• Fertilization fuses two gametes together and doubles the number of

chromosomes to 46 again.
 Definitions
Genes: The units that specify an organism’s inherited characters.
Chromatin: A DNA-protein complex which is organized into a long
thin fiber
Chromosome: The package that formed from a condensed, coiled
and folded chromatin.

Chromatids: Two sister arms (chromatids) formed from each duplicated

chromosome. They contain identical copies of the chromosome’s DNA

Centromere: The narrow region at which the chromosomal strands

are connect together.
Mitosis: Is the division process which forms two daughter nuclei
Cytokinesis: Is the division stage of the cytoplasm which
usually follow the mitosis.
Meiosis: A division process that occurs In the gonads and yields
four daughter cells, each with half the chromosomes of the parent.
A. Mitosis: is usually include five sub-phases:
 Prophase,
 Prometaphase,
 Metaphase,
 Anaphase,
 Telophase.

• By late interphase (G2), the

chromosomes have been
duplicated but are loosely
packed.

• The centrosomes have been

duplicated and begin to organize
microtubules into an aster
(“star”).
1) Prophase, the chromosomes are tightly coiled, with
sister chromatids joined together, The nucleoli
disappear. The mitotic spindle begins to form and
appears to push the centrosomes away from each
other towards opposite ends (poles) of the cell.

2) Prometaphase, the nuclear envelope fragments

and microtubules from one pole attach to one of
two kinetochores (special regions of the
centromere) while microtubules from the other pole
attach to the other kinetochore.

3) Metaphase, the spindle fibers push the sister

chromatids until they are all arranged at the
imaginary plane equidistant between the poles,
defining metaphase.

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• Anaphase, the centromeres divide, result in
separating the sister chromatids. Each is then
pulled toward the pole to which it is attached
by spindle fibers. By the end, the two poles
have equivalent collections of chromosomes.

• Telophase, the cell continues to elongate as

free spindle fibers from each centrosome
push off each other.

1) Two nuclei begin to form, surrounded by the

fragments of the parent’s nuclear envelope.
2) Chromatin becomes less tightly coiled.
3) Cytokinesis, begins as the division of the
cytoplasm occurs.
31
B. The cytokinesis:

divides the cytoplasm:

• Cytokinesis (division of the cytoplasm)

typically follows mitosis.

• Contraction of the cell pinches the cell

into two new cells

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 Cell Cycle

Interphase Division process

Mitosis Cytokinesis

G1 S G2

Prophase Prometaphase Metaphase Anaphase Telophase

 Fertilization and meiosis alternate in sexual life cycles

 A life cycle of an organism is the generation-to-generation sequence of stages

in its reproductive history.

 It starts at the conception of an organism until it produces its own offspring.

 In humans, each somatic cell (all cells other than sperm or ovum) has 46
chromosomes.

 These homologous chromosome pairs carry genes that control the same
inherited characters.

 A karyotype display of the 46 chromosomes shows 23 pairs of chromosomes,

each pair with the same length, centromere position, and staining pattern.
The Karyotype :

It is a display of an individual’s chromosomes that arranged according to size

and shapes)

Fig. 13.3, Page 237 36

 Chromosomes (sex and autosomes)
• An exception to the rule of homologous chromosomes is found in the sex
chromosomes, the X and the Y.

• The pattern of inheritance of these chromosomes determine an individual’s

sex.
– Human females have a homologous pair of X chromosomes (XX).
– Human males have an X and a Y chromosome (XY).

• The other 22 pairs are called autosomes.

• We inherit one chromosome of each homologous pair from each parent.

– The 46 chromosomes in a somatic cell can be viewed as two sets of 23, a maternal
set and a paternal set.

• Sperm cells or ova (gametes) have only one set of chromosomes - 22

autosomes and an X or a Y.

• A cell with a single chromosome set is haploid.

– For humans, the haploid number of chromosomes is 23 (n = 23).
• A haploid sperm reaches and fuses with a haploid ovum.

• The fertilized egg (zygote) now has a diploid set of chromosomes from the
maternal and paternal family lines.

• The zygote and all cells with two sets of chromosomes are diploid cells
46 (2n = 46).

• As an organism develops from a zygote to a sexually mature adult, the zygote’s

genes are passes on to all somatic cells by mitosis.

• Gametes, which develop in the gonads, are not produced by mitosis.

• Instead, gametes undergo the process of meiosis in which the chromosome

number is halved.
– Human sperm or ova have a haploid set of 23 different chromosomes, one from
each homologous pair.
 FERTILIZATION
• Fertilization restores the diploid
condition by combining two haploid
sets of chromosomes.
• Fertilization and meiosis alternate in
sexual life cycles.

– Gametes, produced by meiosis, are

the only haploid cells.

– Gametes undergo no divisions

themselves, but fuse to form a diploid
zygote that divides by mitosis to
produce a multicellular organism

39
 Meiosis (Reduction Division)
Reduces chromosome number from diploid to haploid :

 Many steps of meiosis resemble steps in mitosis.

 Both are preceded by the replication of
chromosomes.
 However, in meiosis, chromosomes replicate once
followed by two consecutive cell divisions, meiosis I
and meiosis II, which results in four daughter cells.
 Each final daughter cell has only half chromosomes
number (haploid (.
 Meiosis reduces chromosome number by copying
the chromosomes once, but dividing twice.
 The first division (meiosis I) separates homologous
chromosomes.
 The second (meiosis II) separates sister chromatids.

40
 2- Meiosis Division (Reduction Division)

Occurs in two steps

A)- Meiosis I B)- Meiosis II

- Separate homologous - No further replication of
chromosomes. chromosomes.
-Occurs in the newly resulting
- Results in 2 haploid cells with
cells from Meiosis I.
replicated chromosomes.
(4 haploid cells)

It occurs mainly in sex gonads to form Gametes (sperms and ova)

Each of the resulting cells has half number of chromosomes of the original cell
(23 in human). Thus, it called Reduction Division

41
Meiosis
A)- Meiosis I: is very similar to mitosis.

1)- interphase the chromosomes are

replicated to form sister chromatids.

2)- Prophase I, the chromosomes condense and homologous

chromosomes pair up to form tetrads.
• Homologous chromosomes attached together (synapsis ‫ا‬
– Chromatids of homologous chromosomes are crossed (at
chiasmata) and segments of the chromosomes are
exchanged (Crossing Over).
2)- Metaphase I, the tetrads are all arranged at the metaphase plate.
– Microtubules from one pole are attached to the kinetochore of one chromosome
of each tetrad, while those from the other pole are attached to the other.

3)- Anaphase I,
the homologous chromosomes separate and are pulled toward opposite
poles.
5)- Telophase I, movement of homologous
chromosomes continues until there is a haploid
set at each pole.
– Each chromosome consists of linked sister
chromatids.

• Cytokinesis by the same

mechanisms as mitosis
usually occurs simultaneously.
• In some species, nuclei
may reform, but there is
no further replication
of chromosomes.
B)- Meiosis II
1)- Prophase II a spindle apparatus forms, attaches to kinetochores of each
sister chromatids, and moves them around.
2)- Metaphase II, the sister chromatids are arranged at the metaphase plate.
3)- Anaphase II, the centromeres of sister chromatids separate and the separate sisters
travel toward opposite poles.

47
4)- Telophase II, separated sister chromatids
arrive at opposite poles.
– Nuclei form around the chromatids.

• Cytokinesis separates the cytoplasm.

• At the end of meiosis, there are four haploid
daughter cells.
 Crossing over
Chiasma

Recombinant Chromosomes
 Crossing over
-Occurs during prophase I.

-The two homologous chromosomes joint together very

closely.

-Two non-sister chromatids of the homologous

chromosomes are crossed over at a chiasma point and
exchange corresponding segments.

-The resulting chromosomes are called “recombinant

chromosomes”.

-It is important in genetic variation in sexual life cycle.

Sexual life cycles produce genetic variation among offspring

• Three mechanisms contribute to genetic variation :

1) independent assortment
2) crossing over
3) random fertilization

1)- Independent assortment: of chromosomes contributes to genetic

variability due to the random orientation of tetrads at the metaphase plate.

– There is a fifty-fifty chance

that a particular daughter cell of meiosis I
will get the maternal chromosome of a
certain homologous
pair and a fifty-fifty
chance that it will
receive the paternal
chromosome.

52
 • Independent assortment alone would find
each individual chromosome in a gamete
that would be exclusively maternal or
paternal in origin.

3)- Crossing over:

Homologous portions of two non-sister
chromatids exchange places, producing
recombinant chromosomes which
combine genes inherited from each
parent.

2- The random fertilization: it adds to the

genetic variation arising from meiosis.
• Any sperm can fuse with any egg.

53
Fig. 13.10
• Mitosis produces two identical daughter cells, but meiosis produces 4 very different
cells.

54
Comparison between Mitosis and meiosis

55
• Independent assortment of chromosomes contributes to
genetic variability due to the random orientation of tetrads at
the metaphase plate.

– There is a fifty-fifty chance that a particular daughter cell of

meiosis I will
get the maternal
chromosome of a
certain homologous
pair and a fifty-fifty
chance that it will
receive the paternal
chromosome.
• Each homologous pair of chromosomes is positioned
independently of the other pairs at metaphase I.

• Therefore, the first meiotic division results in independent

assortment of maternal and paternal chromosomes into
daughter cells.

• The number of combinations possible when chromosomes

assort independently into gametes is 2n, where n is the haploid
number of the organism.

– If n = 3, there are eight possible combinations.

– For humans with n = 23, there are 223 or about 8 million
possible combinations of chromosomes.
• Independent assortment alone
would find each individual
chromosome in a gamete that
would be exclusively maternal
or paternal in origin.

• However, crossing over

produces recombinant
chromosomes which combine
genes inherited from each
parent.
Cell Death mechanisms
Apoptosis and Necrosis
 Type of Cell Death
• The body is very good at maintaining a constant
number of cells. So there has to exist
mechanisms for ensuring other cells in the body
are removed, when appropriate.
• Two forms
– Apoptosis - suicide - programmed cell death
– Necrosis - killing - decay and destruction
Cell Death -occurs more often than one imagines!
a) Most embryo development involves programmed cell death.

18_18_sculpts_digits.jpg
 18_19_tadpole_frog.jpg
b) The tail of the tadpole is absorbed via apoptosis.

Also, in adult multicellular organisms cell death is a regular occurrence. In humans EACH HOUR
we lose many many BILLIONS of cells via apoptosis. Most of these are healthy cells which have
no defects. WHY?
Development and regulation controls.
i.e. B and T cells are removed that do not pass certain tests.
Apoptosis results in a quick and clean cell death, without damaging its
neighbours, or eliciting an immune response. Every cell is equipped with the
‘cell death pathway’. Apoptosis is an intracellular proteolytic pathway. The DNA
is broken into small 200 bp units.

18_20_Apoptosis_.jpg

The cytoplasm shrinks. The mitochondria release cytochrome c. The outer

surface of the plasma membrane gets coated with a different sugar - one that
macrophages can sense and phagocytose.
Cellular symptoms of Necrosis and Apoptosis
 Necrosis

Necrotic organ and tissues

 Caspases
• Proteins which degrade other proteins are employed by
apoptosis – caspases

• Made as inactive precursors – procaspases

• These are activated by other proteins when the right

signal is received

• One caspase cleaves the lamin proteins resulting in the

irreversible breakdown of the nuclear membrane.
18_21_proteolytic_cas.jpg
Apoptotic signaling
 Control of cell numbers and cell size
• Three processes operate to control the eventual form
a body part takes
– Cell growth
– Cell division
– Cell death
• Single celled organisms grow as fast as they are able
to limited by factors such a food availability
• Multicellular organisms receive signals from
other cells in the body

• These signals can be classified into three

catergories
– Mitogens - these allow the cell to enter the cell
cycle
– Growth factors - increase in cell mass
– Survival factors - suppress apoptosis
18_28_regulating_Bcl2.jpg
 Inflammasome
• The inflammasome are innate immune system
receptors and sensors that regulate the activation of
caspase-1 and induce inflammation in response to
infectious microbes and molecules derived from host
proteins.
• They have been implicated in a host of inflammatory
disorders.
• In the case of dysregulation of inflammasome
activation, an assortment of major diseases, such as
cancer, autoimmune, metabolic and neurodegenerative
diseases may arise
Inflammasomes are important signaling complexes that play a
critical role in innate immunity, the body’s first line of defense
against foreign infectious organisms and cell damage.
They also potentiate the adaptive immune response.
Inflammasomes are molecular complexes comprised of three
basic proteins:

- A sensor molecule, which may include NLRP1, NLRP2, NLRP3,

NLRC4, AIM2, and Pyrin (NLRP3 best known)
- Adaptor ASC (apoptosis-associated speck-like protein containing a
caspase recruitment domain or CARD)
-Pro-caspase 1

In the presence of harmful pathogens or internal stressors, the protein

components assemble into an inflammasome. Each of the sensor molecules
respond to different stimuli, and create a unique inflammasome, which is
named by the sensor molecule (i.e. NLRP3 Inflammasome).
Inflammasome complex formation
• Inflammasomes are cytosolic multiprotein oligomers
of the innate immune system responsible for the
activation of inflammatory responses.
• Activation and assembly of the inflammasome
promotes proteolytic cleavage, maturation and
secretion of pro-inflammatory cytokines interleukin 1β
(IL-1β) and interleukin 18 (IL-18), as well as cleavage
of Gasdermin-D.
• The N-terminal fragment resulting from this cleavage
induces a pro-inflammatory form of programmed cell
death distinct from apoptosis, referred to as pyroptosis,
and is responsible for secretion of the
mature cytokines, presumably through the formation
of pores in the plasma membrane.
 Gout-inflammasome induced immune inflammatory
disorder

• Gout is an inflammatory disease caused by

monosodium urate crystal deposition in various tissues
around the body. It causes clinical symptoms, such as
acute monoarthritis.
• It leads to deposition of monosodium urate crystals
inside joints, which triggers an acute inflammatory
response by the NLRP3 inflammasome.
• Monosodium urate crystals can activate the NLRP3
inflammasome, both in vitro (in a lab), and in
vivo (inside a patient’s body).
 AUTOPHAGY
Autophagy (or autophagocytosis) (meaning
"self-devouring”, meaning "hollow") is the
natural, regulated mechanism of the cell that
removes unnecessary or dysfunctional
components. It allows the orderly degradation
and recycling of cellular components.

Autophagy is an intracellular degradation

system that delivers cytoplasmic constituents
to the lysosome.
Autophagy process
Autophagy
Thank you