CELL CYCLE

By- Dr. Ishita Singhal

MDS I YEAR
 INDEX
 Introduction
 Phases
 Control Of Cell Growth And Differentiation
 The Proliferative Potential Of Different Cell Types
 Normal Cell Proliferation
 Regulation Of Eukaryotic Cell Cycle
 Checkpoints
 Insensitivity To Growth Inhibitory Signals
 Role In Tumor Formation
 References
INTRODUCTION
• The cell cycle, or cell-division cycle, is the series of events
that take place in a cell leading to duplication of its DNA (DNA
replication) and division of cytoplasm and organelles to produce
two daughter cells.

• The cell-division cycle is a vital process by which a single-

celled fertilized egg develops into a mature organism, as well as
the process by which hair, skin, blood cells, and some internal
organs are renewed.

• Most cancers are in essence caused by deregulation of the cell

cycle, and many oncogenes and tumor suppressor genes are
intrinsic components of the cell cycle or can influence its
• In bacteria, which lack a cell nucleus, as in prokaryotes, the cell
cycle extends from the end of cell division to the beginning of DNA
replication and then the splitting of the bacterial cell into two
daughter cells.
• In cells with a nucleus, as in eukaryotes, the cell cycle is also
divided into two main stages: 
During interphase, the cell grows, accumulating nutrients
needed for mitosis, and undergoes DNA replication preparing it for
cell division.
During the mitotic phase (including mitosis and cytokinesis), the
replicated chromosomes and cytoplasm separate into two new
daughter cells.
• To ensure the proper division of the cell, there are control
mechanisms known as cell cycle checkpoints.
PHASES
• The eukaryotic cell cycle consists of four distinct phases: 
G0 Phase
Interphase
o G1 Phase
o S Phase
o G2 Phase
M Phase 
o Prophase
o Metaphase
o Anaphase
o Telophase
Cytokinesis Phase
 PHAS SYMBO
STATE DESCRIPTION
E L

RESTING Gap 0 G0 A phase where the cell has left the cycle and has stopped dividing.

Cells increase in size in Gap 1. The G1 checkpoint control mechanism

Gap 1 G1 ensures that everything is ready for DNA synthesis. It takes about 8
hours.

INTER- Synthesi
s
S DNA replication occurs during this phase. It takes about 7 to 8 hours.
PHASE

During the gap between DNA synthesis and mitosis, the cell will
continue to grow. The G2 checkpoint control mechanism ensures that
Gap 2 G2
everything is ready to enter the M (mitosis) phase and divide. It takes
about 4 hours.

Cell growth stops at this stage and cellular energy is focused on the
CELL orderly division into two daughter cells. A checkpoint in the middle of
Mitosis M
DIVISION mitosis (Metaphase Checkpoint) ensures that the cell is ready to
complete cell division. It takes about 1 hour.
 G0 PHASE
• G0 is a resting phase where the cell has left the cycle and has stopped
dividing.
• The word "post-mitotic" is sometimes used to refer to both
quiescent and senescent cells.
• Non-proliferative (non-dividing) cells in
multicellular eukaryotes generally enter the quiescent G0 state from
G1 and may remain quiescent for long periods of time, possibly
indefinitely (as is often the case for neurons). This is very common for
cells that are fully differentiated.
• Cellular senescence occurs in response to DNA damage and external
stress that would make a cell's progeny nonviable; it is often a
 INTERPHASE

• It is also called preparatory phase or intermitosis.

• Interphase is a series of changes that takes place in a newly formed cell and its
nucleus, before it becomes capable of division again.
• Typically interphase lasts for at least 91% of the total time required for the cell
cycle.
• Interphase proceed in three stages:
o G1 PHASE
o S PHASE
o G2 PHASE
 G1 PHASE
• The first phase within interphase, from the end of the previous M
phase until the beginning of DNA synthesis, is called G1.
• During this phase, the biosynthetic activities of the cell, which slowed
down during M phase, resume at a high rate and the cell increases its
supply of proteins and the number of organelles, and grows in size.
• In G1 phase, a cell has three options:
1. To continue cell cycle and enter S phase
2. Stop cell cycle and enter G0 phase for undergoing differentiation
3. Become arrested in G1 phase hence it may enter G0 phase or re-
enter cell cycle.
 S PHASE

• The ensuing S phase starts when DNA synthesis commences; when it

is complete, all of the chromosomes have been replicated, i.e., each
chromosome consists of two sister chromatids.
• Thus, during this phase, the amount of DNA in the cell has doubled.
• Rates of RNA transcription and protein synthesis are very low during
this phase.
 G2 PHASE

• G2 phase occurs after DNA replication and is a period of protein

synthesis and rapid cell growth to prepare the cell for mitosis.
• During this phase microtubules begin to reorganize to form a spindle.
• Before proceeding to mitotic phase, cells must be checked at the G2
checkpoint for any DNA damage the chromosomes.
• The G2 checkpoint is mainly regulated by the tumor protein p53.
• If the DNA is damaged, p53 will either repair the DNA or trigger the
apoptosis of the cell.
 MITOTIC PHASE

• Mitosis is the process by which a eukaryotic cell separates the chromosomes

in its cell nucleus into two identical sets in two nuclei (karyokinesis).
• During the process of mitosis the pairs of chromosomes condense and attach
to microtubules that pull the sister chromatids to opposite sides of the cell.
• It is a relatively short period of the cell cycle and is complex and highly
regulated.
• Errors in mitosis can result in cell death through apoptosis or cause
mutations that may lead to cancer.
• The sequence of events is divided into phases, corresponding to the
completion of one set of activities and the start of the next.
• These phases are sequentially known as:
o Prophase
o Metaphase
o Anaphase
o Telophase
 PROPHASE

• The nuclear envelope is broken down, long strands of chromatin

condense to form shorter more visible strands called chromosomes,
the nucleolus disappears, and microtubules attach to the
chromosomes at the kinetochores present in the centromere.
• Microtubules associated with the alignment and separation of
chromosomes are referred to as the spindle and spindle fibers.
• Chromosomes will also be visible under a microscope and will be
connected at the centromere.
 METAPHASE
• In metaphase, the centromeres of the chromosomes convene
themselves on the metaphase plate (or equatorial plate), an
imaginary line that is equidistant from the two centrosome poles and
held together by complex complexes known as cohesins.
• Chromosomes line up in the middle of the cell by microtubule
organizing centers pushing and pulling on centromeres of both
chromatids thereby causing the chromosome to move to the center.
• At this point the chromosomes are still condensing and the spindle
fibers have already connected to the kinetochores.
• Now, the chromosomes are ready to split into opposite poles of the
cell towards the spindle to which they are connected.
 ANAPHASE
• Once the final chromosome is properly aligned and attached the final
signal dissipates and triggers the abrupt shift to anaphase and this is
caused by the activation of the anaphase-promoting complex .
• One of these proteins that is broken down is securin which through its
breakdown releases the enzyme separase that cleaves the cohesin
rings holding together the sister chromatids thereby leading to the
chromosomes separating.
• After the chromosomes line up in the middle of the cell, the spindle
fibers will pull them apart chromosomes are split apart as the sister
chromatids move to opposite sides of the cell, this makes the cell and
plasma elongated by non-kinetochore microtubules.
 TELOPHASE

• Telophase is the last stage of the cell cycle in which a cleavage furrow
splits the cells cytoplasm and chromatin.
• This occurs through the synthesis of a new nuclear envelopes that
forms around the chromatin gathered at each pole and the
reformation of the nucleolus as the chromosomes decondense their
chromatin back to the loose state it possessed during interphase.
• The division of the cellular contents is not always equal and can vary
by cell type.
 CYTOKINESIS PHASE

• Mitosis is immediately followed by cytokinesis, which divides the

nuclei, cytoplasm, organelles and cell membrane into two cells
containing roughly equal shares of these cellular components.
• Mitosis and cytokinesis together define the division of the mother cell
into two daughter cells, genetically identical to each other and to their
parent cell.
• This accounts for approximately 10% of the cell cycle.
CONTROL OF CELL GROWTH
AND DIFFERENTIATION
• Entry of new cells into a tissue population is largely determined by
their proliferation rate, while cells can leave the population either
by cell death or differentiation into another cell type.

• Cell proliferation can be stimulated by intrinsic growth factor, injury,

cell death, or even mechanical deformation of tissues.

• The biochemical mediators and /or mechanical stressors present in

the local micro-environment can either stimulate or inhibit cell
growth. The excess or deficiency of these can result in net cell
growth.

• Although growth can be accomplished by shortening the length of

the cell cycle or decreasing the rate of cell loss.
THE PROLIFERATIVE
POTENTIAL OF DIFFERENT
CELL TYPES
• The cells of the body are divided into three groups on the basis
of their regenerative capacity and their relationship to the cell
cycle:
Labile cells - Cells of these tissues are continuously being lost
and replaced by maturation from stem cells and by proliferation
of mature cells.
E.g.- epidermis and GI Tract.
Stable cells - Cells of these tissues are quiescent and have
only minimal replicative activity in their normal state.
E.g.- hepatocytes.
Permanent cells - Cells of these tissues are considered to be
terminally differentiated and non-proliferative in postnatal life.
E.g.- neurons and cardiac myocytes.
NORMAL CELL
PROLIFERATION
• Entry and progression of cells through the cell cycle are controlled
by changes in the levels and activities of a family of proteins called
cyclins.

• The levels of the various cyclins increase at specific stages of the

cell cycle, after which they are rapidly degraded as a cell moves on
through the cycle.

• Cyclins accomplish their regulatory functions by complexing with

constitutively synthesized protein called cyclin dependant kinase.

• Different combinations of cyclins and CDKS are associated with each

of the important transitions in the cell cycle and they exert their
effects by phosphorylating a selected group of protein substrate.
REGULATION OF
EUKARYOTIC CELL CYCLE
 • Regulation of the cell cycle involves processes crucial to the
survival of a cell, including the detection and repair of genetic
damage as well as the prevention of uncontrolled cell division.

• The molecular events that control the cell cycle are ordered and
directional; that is, each process occurs in a sequential fashion
and it is impossible to "reverse" the cycle.

• Lim Shuhui and Kaldis Philipp (2013) proofed that CDKs, cyclins and CKIs
are more than just regulators of the cell cycle. They are multifaceted proteins
in processes that are distinct from the main events in cell division. However,
rather than labelling these as ‘cell cycle-independent roles’, it should be
appreciated that the majority of these emerging functions are closely
intertwined with the cell cycle.

Lim Shuhui and Kaldis Philipp. CDKs, cyclins and CKIs: roles beyond cell cycle regulation. Development. 2013; 140: 3079-3093.
 ROLE OF CYCLINS AND CDKS

• Cyclins form the regulatory subunits and CDKs the catalytic subunits
of an activated heterodimer.
• Cyclins have no catalytic activity and CDKs are inactive in the absence
of a partner cyclin.
• When activated by a bound cyclin, CDKs perform a common
biochemical reaction called phosphorylation that activates or
inactivates target proteins to orchestrate coordinated entry into the
next phase of the cell cycle.
• CDKs are constitutively expressed in cells whereas cyclins are
synthesised at specific stages of the cell cycle, in response to various
 INHIBITORS
• Two families of genes, the cip/kip (CDK interacting protein/Kinase
inhibitory protein) family and the INK4a/ARF (Inhibitor of Kinase
4/Alternative Reading Frame) family, prevent the progression of the
cell cycle, because these genes are instrumental in prevention of
tumor formation, they are known as tumor suppressors.
• The cip/kip family includes the genes p21, p27 and p57.
• p21 is activated by p53 (which, in turn, is triggered by DNA damage
e.g. due to radiation).
• p27 is activated by Transforming Growth Factor of β (TGF β), a growth
inhibitor.
• The INK4a/ARF family includes p16INK4a, which binds to CDK4 and
arrests the cell cycle in G1 phase, and p14ARF which prevents p53
CHECKPOINTS
• Cell cycle checkpoints consist of a network of regulatory proteins
that monitor and dictate the progression of the cell through the
different stages of the cell cycle.

• Checkpoints prevent cell cycle progression at specific points,

allowing verification of necessary phase processes and repair of
DNA damage.

• The cell cannot proceed to the next phase until checkpoint

requirements have been met.

• There are several checkpoints to ensure that damaged or

incomplete DNA is not passed on to daughter cells.
1. The G1/S checkpoint:- G1/S transition is a rate-limiting step in
the cell cycle and is also known as restriction point. This is where
the cell checks whether it has enough raw materials to fully
replicate its DNA. An unhealthy or malnourished cell will get stuck
at this checkpoint.
2. The G2/M checkpoint:- G2/M checkpoint is where the cell
ensures that it has enough cytoplasm and phospholipids for two
daughter cells. It also checks to see if it is the right time to
replicate.
3. The metaphase (mitotic) checkpoint:- In this checkpoint, the
cell checks to ensure that the spindle has formed and that all of
the chromosomes are aligned at the spindle equator before
anaphase begins.
• Failure to adequately monitor the fidelity of DNA replication leads to the
accumulation of mutations and possible malignant transformation.

• Many types of cancer are caused by mutations that allow the cells to
speed through the various checkpoints or even skip them altogether,
because these cells have lost their checkpoints, any DNA mutations that
may have occurred are disregarded and passed on to the daughter cells.

• Aside from cancer cells, many fully differentiated cell types no longer
replicate so they leave the cell cycle and stay in G0 until their death.
Thus removing the need for cellular checkpoints.

• Barnum KJ and O’Connell MJ (2016) stated that cell cycle checkpoints share the
feature of detecting a defect in the division program, and then sending signals forward
to alter the oscillations of CDK activity and therefore cell cycle events.

Barnum KJ and O'Connell MJ. Cell cycle regulation by checkpoints. Methods Mol Biol. 2014; 1170:29-40.
INSENSITIVITY TO GROWTH
INHIBITORY SIGNALS
• Tumor suppressor genes encode proteins that inhibit cellular
proliferation by regulating the cell cycle. Unlike oncogenes, both
copies of the gene must be dysfunctional for tumor
development to occur.

• The following describes tumor suppressor genes, whose loss of

function contributes to unregulated cell growth:
RB Gene: Governor of the Cell Cycle
TP53 Gene: Guardian of the Genome
Transforming Growth Factor-β Pathway
Contact Inhibition, NF2, and APC
 RB GENE: GOVERNOR OF THE CELL CYCLE
• Rb exerts antiproliferative effects by controlling the G1- to-S transition
of the cell cycle. In its active form, Rb is hypophosphorylated and binds
to E2F transcription factor. This interaction prevents transcription of
genes like cyclin E that are needed for DNA replication, and so the cells
are arrested in G1.
• Growth factor signaling leads to cyclin D expression, activation of the
cyclin D-CDK4/6 complexes, inactivation of Rb by phosphorylation, and
thus release of E2F.
• Loss of cell cycle control is fundamental to malignant transformation.
Almost all cancers have a disabled G1 checkpoint due to mutation of
either RB or genes that affect Rb function, such as cyclin D, CDK4, and
CDKIs.
 TP53 GENE: GUARDIAN OF THE GENOME
• The p53 protein is the central monitor of stress in the cell and can
be activated by anoxia, inappropriate oncogene signaling, or DNA
damage. Activated p53 controls the expression and activity of
genes involved in cell cycle arrest, DNA repair, cellular senescence,
and apoptosis.
• DNA damage leads to activation of p53 by phosphorylation.
• Activated p53 drives transcription of p21, which prevents Rb
phosphorylation, thereby causing a G1-S block in the cell cycle.
This pause allows the cells to repair DNA damage.
• If DNA damage cannot be repaired, p53 induces cellular
senescence or apoptosis.
 TRANSFORMING GROWTH FACTOR-Β
PATHWAY
• TGF-β inhibits proliferation of many cell types by activation of growth-
inhibiting genes such as CDKIs and suppression of growth-promoting
genes such as MYC and encoding cyclins.

• TGF-β function is compromised in many tumors by mutations in its

receptors (colon, stomach, endometrium) or by mutational
inactivation of SMAD genes that transduce TGF-β signaling (pancreas).
 CONTACT INHIBITION, NF2 AND APC
• E-cadherin maintains contact inhibition, which is lost in malignant
cells.
• APC gene exerts antiproliferative actions by regulating the destruction
of the cytoplasmic protein β-catenin. With a loss of APC, β-catenin is
not destroyed, and it translocates to the nucleus, where it acts as a
growth-promoting transcription factor.
• In familial adenomatous polyposis syndrome, inheritance of a germ
line mutation in the APC gene and sporadic loss of the sole normal
allele causes the development of hundreds of colonic polyps at a
young age. Inevitably, one or more of these polyps evolves into a
colonic cancer.
ROLE IN TUMOR FORMATION
• A disregulation of the cell cycle components may lead to tumor
formation.

• When some genes like the cell cycle inhibitors, RB, p53 etc.
mutate, they may cause the cell to multiply uncontrollably,
forming a tumor.

• Thus there is a net increase in cell number as the number of

cells that die by apoptosis or senescence remains the same.

• The duration of cell cycle in tumor cells is equal to or longer

than that of normal cell cycle.
• The cells which are actively undergoing cell cycle are targeted in
cancer therapy as the DNA is relatively exposed during cell
division and hence susceptible to damage by drugs or radiation.

• This fact is made use of in cancer treatment by a process known

as debulking, a significant mass of the tumor is removed which
pushes a significant number of the remaining tumor cells from
G0 to G1 phase .

• Radiation or chemotherapy following the debulking procedure

kills these cells which have newly entered the cell cycle.
 REFERENCES
• ROBBINS BASIC PATHOLOGY 9TH EDITION

• Barnum KJ and O'Connell MJ. Cell cycle regulation by

checkpoints. Methods Mol Biol. 2014; 1170:29-40.

• Lim Shuhui and Kaldis Philipp. CDKs, cyclins and CKIs: roles
beyond cell cycle regulation. Development. 2013; 140: 3079-
3093.
THANKYOU