GOOD MORNING

CONTENTS
Introduction
Definition of cell cycle
Division of cell cycle
Interphase with its subdivision
Mitosis and its stages
Cytokinesis
Regulation of cell cycle
Steps in cell cycle
What is checkpoint
Checkpoint within cell cycle
Mitotic catastrophe
conclusion
 INTRODUCTION

Cells are the simplest unit of life capable of independent

existence and reproduction.
 Cells have the ability to make nearly identical copies of
themselves by the process of cell division ,a process which is
essential for continuation of life.

 There are variety of reason that causes cell to divide:

• Multicellular organism grow in size and complexity by making
more cells.
• Old and damaged cells are continuosly replaced by division of
cells.
• Single celled organism such as bacteria divide to make new
independent organisms.
Two events are required for succesful cell
reproduction.:
 first,the parent cell must ensure that each new
daughter cell receive a complex copy of its hereditary
information.this information is transmitted in form of
complex molecule called DNA & directs various activities
of cell throughout its life.

 The second requirement is partitioning of cytoplasm

between two daughter cells.

These two events occur through the process of CELL

CYCLE.
DEFINITION OF CELL CYCLE:
The progression of biochemical and
morphological phases and events that occur in
a cell during successive cell replication or
nuclear replication events.canonically cell
cycle comprise the replication & segregation of
genetic material followed by division of cell.
 DIVISION OF CELL CYCLE:

• Cell cycle in eukaryotic cells ( cells that have a

nucleus) have been divided into :
 Interphase:
when cell contents are duplicated ,
 Mitosis:
when duplicated chromosomes are
segregated from each other.
 Cytokinesis
when the cell physically divides.
 INTERPHASE
• During interphase, the cell grows and replicates its
chromosomes. Interphase accounts for the interval
between consecutive phases of mitosis.

and is subdivided into three phases:

• gap phase 1 (G1)
• , synthesis (S)
• , and gap phase 2 (G2)
• . Interphase is followed by mitosis (nuclear division)
and cytokinesis (cell division)..
• G1 :
phase 1 begins at the completion of
mitosis and cytokinesis and lasts
until the beginning of S phase
.
.This phase is generally the longest
of the four cell cycle phases and is
quite variable in length.
During this phase, the cell chooses
either to replicate its
deoxyribonucleicacid (DNA) or to
exit the cell cycle and enter a
quiescent state (the G0 phase).
• S phase:
Replication of the chromosomes is
restricted to one specific portion of
interphase, called S phase (DNA
synthesis phase), which typically
lasts about 6 h.
In mammalian cells,the start of S
phase—the actual initiation of DNA
synthesis—takes place several
hours after the cell has committed to
carrying out DNA synthesis.
During S phase, each chromosome
replicates exactly once to form a
pair of physically linked sister
chromatids.
• G2 phase:
The portion of interphase that follows S
phase is called gap phase 2. Some
cells can exit the cell cycle from G2
phase, just as they can from G1
phase.

The Microtubule organizing centre must

also be precisely duplicated once per
cell cycle.Microtubules are cytoskeletal
polymers (long hollow fibres of stacked
protein subunits)that help to determine
cell shape during interphase and that
reorganize during mitosis to make a
remarkable apparatus that segregates
the duplicated chromosomes to
opposite ends of the cell.
 The concept of Go phase:-
• Certain kinds of interphase cells
seem to be able to withdraw from
the cycling state during G1 for an
indefinite period without going on to
specialize.
• Many believe that such cells enter
a special sort of standby noncycling
state called Go.
• The term Go is reserved for
quiescent(nonproliferating) cells
that for the time being are out of
cycle.
• However appropriate stimuli are
able to trigger their reentry into G1.
 MITOSIS

•
* mitosis - a process of nuclear
division in eukaryotic cells,
conventionally divided into 4
stages
• prophase,
• metaphase,
• anaphase,
• telophase.
Mitosis conserves chromosome
number by equally allocating
relicated chromosomes to each
of the daughter nuclei
TERMINOLOGY:
The condensed replicated
chromosomes have
several points of interest
chromatid -
• one of two identical
chromosomal strands
into which a chromosome
splits longitudinally
preparatory to cell
division.
• CENTROMERE:a
specialized structure on
the chromosome,
appearing during cell
division as the constricted
central region where the
two chromatids are held
together and form an X
shape.
• Centriole-
• one of a pair of small
cylindrical cell organelle
near the nucleus in
animal cells; composed of
nine triplet microtubules
and form the asters
during mitosis.
• Spindle-
• spindle-shaped structure,
composed of
microtubules,that forms
near the cell nucleus
during mitosis or meiosis
and, as it divides, draws
the chromosomes to
opposite poles of the cell.
•
• The kinetochore is the
point where microtubules
of the spindle apparatus
attach
Stages of cell cycle
 STAGES OF MITOSIS
PROPHASE:

* Duplicated chromosomes start to condense from

the diffused chromatin and become visible as
threadlike structures. Chromosomes continue to
condense and become thicker as prophase
progresses.

• * The nucleolus region, an aggregation of

chromosome bits and concentrated RNA and
protein, of the nucleus will start to disappear.
* The duplicated chromosomes are firmly
attached at their centromeres throughout this
condensation and coiling.

• * Microtubules initiate spindle formation and

determine the poles of the cell. The spindle
apparatus will extend from the poles of the cell
to the center of the cell surrounding the nuclear
region and to the opposite pole of the cell.
• * Some microtubules from each pole of the cell attach
to a protein structure, called the kinetochore, located
in the centromere region of each duplicated
chromosome.

• * Other microtubules overlap each other from poles

through the equator region of the cell.

• * In animal cells, clusters of microtubules form around

the centrioles, which replicated during interphase,
and migrate to the respective poles of the dividing
cell. These regions are called the spindle poles, or
asters.

• * The nuclear membrane degrades in later prophase

into small vesicles, which can be used to synthesis
new nuclear membrane material in the new cells.
 METAPHASE
• The spindle apparatus moves the
chromosomes to the equator of the cell,
aligning the centromeres of each duplicated
chromosome along the equator of the cell.

• * Chromosomes are moved by a

combination of pulling and pushing of
spindle microtubules.

• * The length of the spindle microtubules is

regulated by the kinetochores to facilitate
the alignment of centromeres at the
equator.

• * This alignment of chromosomes along the

equator plane of the cell is called the
metaphase plate
 ANAPHASE
• Early in anaphase, each double chromosome
split at its centromere,allowing its two component
single chromosome to separate from each other.
• Half the number of single chromosome then
approach each pole of cell.
• As the daughter chromosome progress towards
the pole,the kinetochore microtubules attached to
them shorten by undergoing net disassembly at
their polar end
• * Since sister chromatids are identical, each of
the two clusters of chromosomes being pulled to
the two poles of the cell has one copy of each
original chromosome. As the chromosomes are
pulled toward the poles, they begin to lengthen
out.
 TELOPHASE
• * Chromosomes stretch back
out and become indistinct as
chromatin

• * Membrane vesicles form new

nuclear membranes around
each group of chromosomes
(at the two poles)

• * The spindle microtubules

disperse and the spindle
apparatus disappears

• New nucleoli form

 CYTOKINESIS
• Cytokinesis ,the physical division of one
parent cell into two daughters ,begin
during or after chromosome
segregation .

• Mechanism of cytokinesis is quite

variable depending on cell types.

• Most animal cell have an easily

deformable plasma membrane ,and
divide by changing cell
shape,constricting a ring of actin and
myosin filaments to generate a “cleavage
furrow” that pinches the cell into two.
• Plant,fungal and bacterial
cell ,in contrast,are
surrounded by a rigid cell
wall and divide by
synthesizing a new cell
wall or septum that bisect
the parental cell.
 REGULATION OF CELL CYCLE

• Regulation of cell cycle is done

with the help of protein called
Maturation promoting factor.
Maturation promoting factor
consist of two proteins:
 Cdc2(also called as Cdk1),a
32-kilodalton member to the
Cdk family of proteins.
 Cyclin B,a 45-kilodalton
member of cyclin family which
are key regulator of cell cycle.
• Cyclin/Cdc2 and other kinases turned on at mitosis
by cyclin/Cdc2 catalyze a large increase in
phosphorylation (the number of phophates added) of
many cellular proteins ,and these phosphorylation
are thought to alter the properties of those proteins
so as to induce chromosome condensation ,nuclear
envelop disassembly,altered microtubule behaviour
and other events of early mitosis.
• Following cyclin destruction ,Cdc2 is inactivated
and cellular phosphatases(a phosphatases is an
enzyme that removes the phosphate groups
attached by kinases)return the Cdc2 targets to
their dephoshorylated form,leading to nuclear
envelop reassembly,chromosome decondensation
and exit from mitosis.

• Cyclin –Cdk complex acts at different phase of

cell cycle and cell cycle requires an increase in
cyclin-Cdk activity in some phases followed by
decline of that activity in other phases.
 Regulation of different phases of
cell cycle by cyclin-Cdk complexes:
• Regulation of cell cycle is also done through:
 anaphase-promoting complex (APC). (The
APC is also called the cyclosome, and the
complex is often designated as the APC/C.) The
APC/C
• triggers the events leading to destruction of the
cohesins thus allowing the sister chromatids to
separate;
• degrades the mitotic cyclin B.
 p53 is a protein that functions to block the cell cycle if
the DNA is damaged. If the damage is severe this
protein can cause apoptosis (cell death).
• p53 levels are increased in damaged cells. This allows
time to repair DNA by blocking the cell cycle.
• A p53 mutation is the most frequent mutation leading to
cancer

 p27 is a protein that binds to cyclin and cdk blocking

entry into S phase. Reduced levels of p27 predict a
poor outcome for breast cancer patients.
 In addition some inhibitory proteins restrict
progression of cell through the cycle.two such
proteins are p15 & p16.
these protein block activity of Cdk partnes of cyclin
D,preventing progression from G1 to the S phase.

 Another inhibitor of cdks,p21,can act throughout

cell cycle.p21 is under control of tumour suppressor
protein p53,which prevent replication of damaged
DNA.
 BUILDING AN AUTONOMOUS
OSCILLATOR
If cyclin accumulation and destruction
drive the cell cycle,then what is it that
drive cyclin accumulation and
destruction?
cyclin synthesis (by ribosomes
programmed with a pool of stable
cyclin mRNA) occurs at a constant
rate,but cyclin destruction only occurs
in a short bursts at the end of each
cycle.
this leads to “saw tooth”pattern of
cyclin abundance,with gradual
accumulation of cyclin punctuated by
brief episode of cyclin annihilation.
 Cyclin destruction takes place inside a protein
complex called proteasome,which feeds proteins
through a tunnel like interior cavity that chews them
up into small peptides and amino acids.
• This destruction is mediated by conjugation to a small
protein called Ubiquitin.
• Ubiquitin ligase responsible for flagging cyclin is
another protein complex that is dormant much of
time,but is awakened by a process that involves
phosphorylation of several of its protein by active
cyclin Cdk.
• Thus cyclin cdk sows seed of its demise by activating
ubiquitin ligase that flag cyclin for destruction.
 STEPS IN CELL CYCLE
• A rising level of G1-cyclins bind to their Cdks and
signal the cell to prepare the chromosomes for
replication.
• A rising level of S-phase promoting factor (SPF) —
which includes cyclin A bound to Cdk2 — enters the
nucleus and prepares the cell to duplicate its DNA
(and its centrosomes).
• As DNA replication continues, cyclin E is destroyed,
and the level of mitotic cyclins begins to rise (in G2).
• M-phase promoting factor (the complex of mitotic
cyclins with the M-phase Cdk) initiates
– assembly of the mitotic spindle
– breakdown of the nuclear envelope
– condensation of the chromosomes
• These events take the cell to metaphase of mitosis.
• At this point, the M-phase promoting factor activates the
anaphase-promoting complex (APC/C) which
• allows the sister chromatids at the metaphase plate to
separate and move to the poles (= anaphase),
completing mitosis;
• destroys cyclin B. It does this by attaching it to the
protein ubiquitin which targets it for destruction by
proteasomes.
• turns on synthesis of G1 cyclin for the next turn of the
cycle;
• degrades geminin, a protein that has kept the freshly-
synthesized DNA in S phase from being re-replicated
before mitosis
 WHAT IS CHECKPOINT?
• The checkpoints are surveillance mechanism
and quality control of the genome to maintain
genomic integrity. Checkpoint failure often
causes mutations and genomic
dearrangements resulting in genetic
instability. Genetic instability is a major factor
of birth defects and in the development of
many diseases, most notably cancer.
 CHECKPOINTS WITHIN CELL
CYCLE
• Throughout the cell cycle,several internal quality
control mechanism or checkpoints represented by
biochemical pathways control transition between cell
cycle stages.
• The cell cycle stops at several checkpoints and can
only proceed if certain conditions are met,for
example,if the cell has reached a certain size.
• Checkpoints monitor and modulate the progression
of cells through the cell cycle in response to
intracellular or environmental signals.
 G1 phase:
 the cell’s progress through this phase is monitored
by two checkpoints:
 The restriction point,which is sensitive to size of
cell,state of cell’s physiologic processes,and its
interaction with extracellular matrix.
 The G1 DNA-damage checkpoint,which monitors the
integrity of newly replicated DNA.For instance,if the
DNA has irreparable damage,the G1 DNA damage
checkpoint detects the high level of tumour
suppressing protein p53 and it doesnot allow the cell
to enter S phase. The cell will then most likely
undergo apoptosis.
 S phase:
 Presence of S DNA-
damage checkpoint in
this phase monitors
quality of replicating DNA.
 G2 phase:
 two checkpoint monitor
DNA quality:
 G2 DNA damage
checkpoint
 Unreplicated –DNA
checkpoint:prevents the
progression of cell into
the M phase before DNA
synthesis is complete.
 M phase:
 it possess two checkpoints:

 Spindle-assembly
checkpoint,which prevents
premature entry into
anaphase,

 Chromosome –segregation
checkpoint,which prevent the
process of cytokinesis until all
of the chromosomes have
been correctly matched.
CELL CYCLE AND CHECKPOINTS
Mitotic catastrophe caused by
malfunction of cell cycle
checkpoints: lead to tumour
development
Malfunction of any of the three DNA-damage
checkpoint at G1,S & G2 phases of the cell cycle and
spindle assembly checkpoint at M phase may lead to
Mitotic catastrophe.

Mitotic catastrophe is defined as the failure to arrest

the cell cycle before or at mitosis,resulting in aberrant
chromosome segregation.

Under normal condition in these cycles death will

occur by activation of apoptotic cycle.

Cells that fail to execute apoptotic cycle in response

to DNA or mitotic spindle damage are likely to divide
asymmetrically in next round of cell division.
This leads to generation of aneuploid cells(cells
containing abnormal chromosome number).

Thus a mitotic catastrophe may be regarded as one

of the mechanism contributing to oncogenesis.

Malfunction of restriction checkpoint at G1 phase

result in malignant transformation of cells.

This is facilitated by viral proteins of several cancer

causing viruses such as T-antigen of simian
virus(SV40)that binds to pRb.
This binding alters the configuration of pRb-T antigen
complex and renders restriction checkpoint
inoperable,thus facilitating the cell’s progression from
G1 to S phase of cell cycle.
This mechanism of carcinogenesis occurs in
Mesothelioma(cancer of the lining epithelium of pleural
cavities in the thorax),
Osteosarcoma(a type of bone cancer)
Ependymoma(a type of chidhood brain tumour)
• All the checkpoints examined require the services of a
complex of proteins. Mutations in the genes encoding
some of these have been associated with cancer; that
is, they are oncogenes.
• Examples
• p53
• The p53 protein senses DNA damage and can halt
progression of the cell cycle in G1 (by blocking the
activity of CDK). Both copies of the p53 gene must be
mutated for this to fail so mutations in p53 are
recessive, and p53 qualifies as a tumor suppressor
gene. The p53 protein is also a key player in
apoptosis., forcing "bad" cells to commit suicide. So if
the cell has only mutant versions of the protein, it can
live on — perhaps developing into a cancer. More than
half of all human cancers do, in fact, harbor p53
mutations and have no functioning p53 protein.
• ATM
• ATM (="ataxia telangiectasia mutated") gets its
name from a human disease of that name ,
whose patients — among other things — are at
a greatly increased (~100 fold) risk of cancer.
The ATM protein is involved in
• detecting DNA damage, especially Double
strand breaks.
• interrupting (with the aid of p53) the cell cycle
when damage is found;
• maintaining normal telomere length.
• MAD
MAD (="mitotic arrest deficient") genes (there are two)
encode proteins that bind to each kinetochore until a
spindle fiber attaches to it. If there is any failure to
attach, MAD remains and blocks entry into anaphase (by
inhibiting the anaphase promoting complex).

• Mutation in MAD produce a defective protein and failure

of the checkpoint. The cell finishes mitosis but produces
daughter cells with too many or too few chromosomes
(aneuploidy). Aneuploidy is one of the hallmarks of
cancer cells suggesting that failure of the spindle
checkpoint is a major step in the conversion of a normal
cell into a cancerous one.
 CONCLUSION:
• The events of cell cycle are
masterpieces of molecular engineering,
employing distinctive machineries to
generate two cells from one.
• Derangement of cell cycle control
pathways by mutations in somatic cells
make an important contribution to
disease, in particular to cancer.
 REFERENCES
1.Encyclopedia of human biology.vol 2
,Renato dulbecco
2.Ham’s textbook of histology
3.Histology textbook by Ross
4.General pathology 3rd edition by Harshmohan
5.Basic pathology by Kumar cotran Robbins,
7th edition
6.Google search
THANK YOU