Cell Cycle

CONTENTS
• 1 Phases
– 1.1 Resting (G0 phase)
– 1.2 Interphase
• 1.2.1 G1 phase
• 1.2.2 S phase
• 1.2.3 G2 phase
– 1.3 Mitosis (M Phase)

• 2 Regulation of eukaryotic cell cycle

– 2.1 Role of cyclins and CDKs
• 2.1.1 General mechanism of cyclin-CDK interaction
• 2.1.2 Specific action of cyclin-CDK complexes
– 2.2 Inhibitors
 Contd..
• 3 Checkpoints
• 4 Role in tumor formation
• 5 Synchronization of cell cultures
• 6 References
 Cell cycle
• The cell cycle, or cell-division cycle, is the series of
events that take place in a cell leading to its division
and duplication (replication).
 The cell cycle
• The cell cycle can be divided in two brief
periods:
• Interphase—during which the cell grows,
accumulating nutrients needed for mitosis and
duplicating its DNA
• Mitosis (M) phase, during which the cell splits
itself into two distinct cells, often called
"daughter cells".
 PHASES OF CELL CYCLE
• Presynthetic growth phase or G1
• DNA Synthetic phase or S
• Premitotic growth phase or G2
• Mitotic phase or M
• Quiescent phase or G0
PHASES OF CELL CYCLE
MITOSIS
 M PHASE
• M phase is itself composed of two tightly
coupled processes:
• Mitosis, in which the cell's chromosomes are
divided between the two daughter cells
• Cytokinesis, in which the cell's cytoplasm
divides forming distinct cells.
 MEIOSIS

• Meiosis is a process of reductional division in which

the number of chromosomes per cell is halved
• In animals, meiosis always results in the formation of
gametes, while in other organisms it can give rise to
spores.
• As with mitosis, before meiosis begins, the DNA in the
original cell is replicated during S-phase of the cell
cycle.
• Two cell divisions separate the replicated
chromosomes into four haploid gametes or spores.
MEIOSIS I
MEIOSIS II
 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.
 Cyclins and CDKs

Two key classes of regulatory molecules,

determine a cell's progress through the cell
cycle:
– cyclins
– cyclin-dependent kinases (CDKs)
 Role of cyclins and CDKs
• Cyclins form the regulatory subunits & have no catalytic
activity

• CDKs the catalytic subunits of an activated heterodimer;

• 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.
Regulation of cell cycle
 Cyclins and CDKs
• Different cyclin-CDK combinations determine the
downstream proteins targeted.

• CDKs are constitutively expressed in cells whereas cyclins are

synthesized at specific stages of the cell cycle, in response to
various molecular signals.
Cyclins and CDKs
 Inhibitors
• Two families of genes, prevent the
progression of the cell cycle.
– the cip/kip family
• INK4a/ARF (Inhibitor of Kinase 4/Alternative
Reading Frame)
• These genes are instrumental in prevention of
tumor formation, they are known as tumor
suppressors.
Inh ibitors
 Action of inhibitors
• The cip/kip family includes the genes p21, p27 and p57.
They halt cell cycle in G1 phase, by binding to, and
inactivating, cyclin-CDK complexes.

• p21 is activated by p53 (which, in turn, is triggered by

DNA damage eg. due to radiation).

• p27 is activated by Transforming Growth Factor β (TGF

β), a growth inhibitor.
 Action of inhibitors
• The INK4a/ARF family includes p16INK4a, which binds to
CDK4 and arrests the cell cycle in G1 phase, and p14arf which
prevents p53 degradation.

• And the amount of chromosomes are able to double at the

same rate as in phase 2.
 Cell Cycle checkpoints
• Cell cycle checkpoints are used by the cell to monitor and
regulate the progress of the cell cycle.

• Checkpoints prevent cell cycle progression at specific points,

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

• Several checkpoints are designed to ensure that damaged or

incomplete DNA is not passed on to daughter cells.
 Cell cycle checkpoints

• Two main checkpoints exist: the G1/S checkpoint and the

G2/M checkpoint. G1/S transition is a rate-limiting step in the
cell cycle and is also known as restriction point.

• P53 plays an important role in triggering the control

mechanisms at both G1/S and G2/M checkpoints.
Check points
Cell cycle checkpoints
 Regulation
• A cyclin-CDK complex can be regulated by several
kinases and phosphatases, including Wee, and CDK-
activating kinase (CAK), and Cdc25.
• CAK adds an activating phosphate to the complex,
while Wee adds an inhibitory phosphate; the presence
of both activating and inhibitory phosphates renders
the complex inactive.
• Cdc25 is a phosphatase that removes the inhibitor
phosphate added by Wee, rendering the complex
active.
Role in tumor formation
 RB TUMOUR SUPPRESSOR
GENE
• RETINOBLASTOMA is a rare tumor ,affects 1 in
20,000 children
• Knudson proposed a ‘ TWO HIT’ hypothesis for the
development of Retinoblastoma
• Mutations required involve the RB gene located on
chromosome 13q14.
• Cancer develops when cell becomes homozygous for
the mutant allele or loses heterozygosity for the
normal Rb gene.
 Growth factor
• The term growth factor refers to a naturally
occurring substance capable of stimulating cellular
growth, proliferation and cellular differentiation.
• Usually it is a protein or a steroid hormone. Growth
factors are important for regulating a variety of
cellular processes.
• Growth factors typically act as signaling molecules
between cells.
 Examples Of growth factors
• Examples are cytokines and hormones that bind to
specific receptors on the surface of their target
• They often promote cell differentiation and
maturation, which varies between growth factors.
For example, bone morphogenic proteins stimulate
bone cell differentiation, while fibroblast growth
factors and vascular endothelial growth factors
stimulate blood vessel differentiation (angiogenesis)
Growth factor
 p53
• p53 (also known as protein 53 or tumor protein 53),
is a transcription factor which in humans is encoded
by the TP53 gene.
• p53 is important in multicellular organisms, where it
regulates the cell cycle and thus functions as a tumor
suppressor that is involved in preventing cancer. As
such, p53 has been described as "the guardian of the
genome,“
• "the guardian angel gene," and the "master
watchman," referring to its role in conserving
stability by preventing genome mutation.
 RECENT ADVANCES

BCL-2
• Human proto oncogene located on chromosome
– 18.
• Its product is an integral membrane protein
located in the membrane of endoplasmic
reticulum, nuclear envelope and the outer
membrane of mitochondria.
• The gene was discovered as the translocated
locus in B-Cell leukemia.
 Ki-67
• Antigen identified by monoclonal antibody ki-
67 or ki-167 is a protein which in humans is
encoded by the MK-167 gene.
• Ki-67 is a protein which acts as a cellular
marker for proliferation.
• During INTERPHASE this antigen can be
exclusively detected as within the cell nucleus
where as in mitosis most of the protein is
relocated to the surface of the chromosomes.
• It is present during all active phases of the cell
cycles and is absent from resting cells.
 Proliferating Cell Nuclear Antigen
(PCNA)
• It is currently used in the diagnosis of
malignancy as well as in evaluating the
prognosis of the patient.It is small (36kd)
nuclear protein involved in many cellular
processes.
• It plays a crucial role in both DNA replication
and DNA repair
 BIBLIOGRAPHY

• PRINCIPLES OF ORAL PATHOLOGY ROBBINS

• PRINCIPLES OF ANATOMY & PHYSIOLOGY Tortora Derrickson
• A TEXT AND ATLAS OF HISTOLOGY Michael H Ross
• TEXTBOOK OF MEDICAL PHYSIOLOGY Guyton Hall
• TEXTBOOK OF HISTOLOGY Ham’s
• GREY’S ANATOMY Grey
• WIKIPEDIA.COM