CELL CYCLE and its

REGULATION
 CONTENTS

1. INTRODUCTION TO CELL
2. HISTORY
3. CELL CYCLE
4. PHASES OF CELL CYCLE
5. CHECK POINTS
6. CYCLIN-DEPENDENT KINASES
7. TYPES OF CDKS
8. MECHANISM OF CDK INTERACTION
9. REGULATION OF CDK ACTIVITY
10. MEDICAL SIGNIFICANCE
11. CONCLUSION
12. REFERENCE
 INTRODUCTION

 The cell is the basic structural and functional unit of all known living
organisms.
 It is the smallest unit of life that is classified as a living thing, and is
often called the building block of life.
 The cell was discovered by Robert Hooke in 1665.
 The word cell comes from the Latin cella, meaning "small room".
 HISTORY

Leland H. Hartwell, R. Timothy Hunt, and Paul M. Nurse received

the 2001 Nobel Prize in Physiology or Medicine for their complete
description of cyclin and cyclin-dependent kinase mechanisms, which
are central to the regulation of the cell cycle.
Packaging of genetic material in prokaryotes and eukaryotes

prokaryote cell

eukaryote cell

chromosomes
 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 division of the cell into two daughter cells. The repeated process of cell
division, where daughter cells continue to divide to form further generations
of 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, and some internal organs are renewed.
 PHASES OF CELL CYCLE
 The cell cycle consists of four distinct phases namely,
• G1 Phase
• S phase
• G2 phase
• M phase
 INTERPHASE
 Before a cell can enter cell division, it needs to take in nutrients. All of the
preparations are done during interphase. Interphase is a series of changes
that takes place in a newly formed cell and its nucleus, before it becomes
capable of division again.

 It is also called preparatory phase or intermitosis. Previously it was called

resting stage because there is no apparent activity related to cell division.

 Interphase proceeds in three stages, G1, S, and G2, followed by the cycle of
mitosis and cytokinesis. The cell's nuclear chromosomes are duplicated
during S 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 (G indicating
gap). It is also called the growth phase.
 This phase is marked by synthesis of 20 amino acids, which then form
millions of proteins, and later on enzymes that are required in S phase,
mainly those needed for DNA replication.
 Therefore this is the longest phase during which the cells are preparing
for replication.
 S PHASE
 The S phase starts when DNA synthesis commences; when it is complete,
all of the chromosomes have been replicated, i.e., each chromosome has
two (sister) chromatids.
 Thus, during this phase, the amount of DNA in the cell has effectively
doubled, though the ploidy of the cell remains the same. During this phase,
synthesis is completed as quickly as possible due to the exposed base pairs
being sensitive to external factors such as any drugs taken or any mutagens
(such as nicotine).
 Therefore this phase is called as DNA synthesis phase which the DNA is
replicated and a complete copy of each of the chromosome is made.
 G2 PHASE

 A short gap phase, which occurs after s phase and before mitosis.

 The cell then enters the G2 phase, which lasts until the cell enters mitosis.
Again, significant biosynthesis occurs during this phase, mainly involving the
production of microtubules, which are required during the process of mitosis.

 Inhibition of protein synthesis during G2 phase prevents the cell from

undergoing mitosis.
 M PHASE

 This phase is called as mitotic phase[mitosis].

 Mitosis is the process by which a eukaryotic cell separates the

chromosomes in its cell nucleus into two identical sets in two nuclei.

 The process of cell division whereby the chromosomes are

duplicated and distributed equally to the daughter cells is called
mitosis.

 Mitosis mainly takes place in somatic cells of the body like skin,
blood, hair, bone etc.
 Different phases of mitosis

 The M phase has been broken down into several distinct phases,
sequentially known as:
1. Prophase,
2. Metaphase,
3. Anaphase,
4. Telophase

5. Cytokinesis
 1. Prophase

- Chromatin condenses, this causes the chromosomes to begin to

become visible

- Centrosomes separate, moving to opposite ends of the nucleus

- The centrosomes start to form a framework used to separate the two

sister chromatids called the mitotic spindle, that is made of
microtubules

- Nucleolus disappears
 2. Prometaphase

- Nuclear envelope fragments

- Chromosomes become more condensed

- A kinetochore is formed at the centromere, the point where the sister

chromatids are attached

- Microtubules attach at the kinetochores

 3. Metaphase
 The spindle becomes fully developed
 The chromatid pairs place themselves onto individual fibres and are aligned
along the centre of the spindle
 Chromosomes align on an axis called the metaphase plate
 The nuclear membrane has completely gone
 - Note: the spindle consists of microtubules, one attached to each chromosome
 4. ANAPHASE
 The chromatid pairs are split into two
(This is done by movement of the spindle fibres)
 The pairs then travel to opposite ends of the spindle
 The halved chromatids are now called chromosomes
 5. Telophase
• Formation of nuclear membrane and nucleolus
• Short and thick chromosomes begin to elongate to form long and
thin chromatin
• Formation of the cleavage furrow - a shallow groove in the cell
near the old metaphase plate
• Cytokinesis = division of the cytoplasm
 The Cell Cycle Control System
 The sequential events of the cell cycle are directed by a distinct cell cycle
control system, which is similar to a clock
 The clock has specific checkpoints where the cell cycle stops until a go-
ahead signal is received
 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.
 The cell cannot proceed to the next phase until checkpoint requirements
have been met.
 For many cells, the G1 checkpoint seems to be the most important one
 Checkpoint
G1 checkpoint

Control
system
S
G1

M G2

M checkpoint G2 checkpoint
 G0

G1 checkpoint

G1 G1

If a cell receives a go-ahead If a cell does not receive a go-

signal at the G1 checkpoint, the ahead signal at the G1
cell continues on in the cell checkpoint, the cell exits the cell
cycle. cycle and goes into G0, a
nondividing state.
 CYCLIN DEPENDENT KINASE
 Cyclin-dependent kinases (CDKs) are a family of protein kinases first
discovered for their role in regulating the cell cycle.
 They are also involved in regulating transcription, mRNA processing,
and the differentiation of nerve cells.
 CDKs are relatively small proteins, with molecular weights ranging from
34 to 40 kDa, and contain little more than the kinase domain.
 CDK binds a regulatory protein called a cyclin. Without cyclin, CDK has
little kinase activity; only the cyclin-CDK complex is an active .
 CDKs phosphorylate their substrates on serines and threonines, so they
are serine-threonine kinases. There are 9 types of CDK’s
 Regulation of CDK’s
 The three major mechanisms of CDK regulation are, cyclin binding, CAK

phosphorylation, and

 binding of CDK inhibitory subunits (CKIs).

 Cyclin binding
 Cell cycle signals
 Cell cycle controls

 cyclins
 regulatory proteins
 levels cycle in the cell
 Cdk’s
 cyclin-dependent kinases
 phosphorylates cellular
proteins
 activates or inactivates
proteins Now performs
 Cdk-cyclin complex a cell cycle function

 triggers passage through

different stages of cell
cycle
PHOSPHORYLATION
 Kinase activity requires an activating phosphorylation on a threonine
adjacent to the active site. The identity of the CDK-activating kinase
(CAK) that performs this phosphorylation varies across the model
organisms.

 Unlike activating phosphorylation, CDK inhibitory phosphorylation is vital

for regulation of the cell cycle. Various kinases and phosphatases regulate
their phosphorylation state. One of the kinases that place the tyrosine
phosphate is Wee1, a kinase conserved in all eukaryotes.

 CDK INHIBITOR :-A cyclin-dependent kinase inhibitor (CKI) is a

protein that interacts with a cyclin-CDK complex to block kinase activity,
usually during G1 or in response to signals from the environment or from
damaged DNA.
 TYPES AND THEIR ROLE
CDK Cyclin partner Function

Cdk1 Cyclin B Regulate the completion of M phase

Cdk2 Cyclin E G1/S transition

Cdk2 Cyclin A S phase, G2 phase

Cdk3 Cyclin C G1 phase

Cdk4 Cyclin D regulate G1 phase

Cdk5 p35 Transcription

Cdk6 Cyclin D regulate G1 phase

Cdk7 Cyclin H CDK-activating kinase, transcription

Cdk8 Cyclin C Transcription

Cdk9 Cyclin T Transcription

 ROLE IN TUMOR FORMATION
 A disregulation of the cell cycle components may lead to tumor formation.
some genes like the cell cycle inhibitors, RB, p53 etc., when they mutate,
may cause the cell to multiply uncontrollably, forming a tumor.

 Although the duration of cell cycle in tumor cells is equal to or longer than
that of normal cell cycle, the proportion of cells that are in active cell division
(versus quiescent cells in G0 phase) in tumors is much higher than that in
normal tissue.

 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.
Cyclin-dependent kinase inhibitor drugs
Drug CDKs Inhibited

Flavopiridol (Alvocidib) 1, 2, 4, 6, 7, 9

Olomoucine 1, 2, 5

Roscovitine 1, 2, 5

Purvalanol 1, 2, 5

Paullones 1, 2, 5

Butryolactone 1, 2, 5

Thio/oxoflavopiridols 1

Oxindoles 2

Aminothiazoles 4

Benzocarbazoles 4

Pyrimidines 4
 Conclusion
 The cell cycle involves DNA replication followed by cell division to produce two
daughter cells from one parent. It is ordered process which is controlled by the
cell cycle machinery.
 Checkpoints are stages at which the cell cycle may be halted if the
circumstances are not right for cell division. Principal checkpoints occur at the
end of G1 and G2 gap phases.
 The cell cycle is controlled through protein phosphorylation, which is catalyzed
by multiple protein kinase complexes. These complexes consists of cyclins, the
regulatory subunits, and cyciln dependent kinases[CDKS],the catalytic
subunits.
 Different cyclins-CDK complexes control different phases of the cell cycle. In
turn, their activity is regulated through transcriptional control of their synthesis,
alteration of their enzymes activity by inhibitor proteins and by regulation of their
proteolytic destruction.
 CDKs are considered a potential target for anti-cancer medication. If it is
possible to selectively interrupt the cell cycle regulation in cancer cells by
MEIOSIS
 Meiosis
 The form of cell division by which gametes, with
half the number of chromosomes, are produced.
 Diploid (2n)  haploid (n)

 Meiosis is sexual reproduction.

 Two divisions (meiosis I and meiosis II).

 Fertilization

 The fusion of a sperm and egg to form a zygote.

 A zygote is a fertilized egg

sperm
n=23 n=23
egg
2n=46
zygote
 Meiosis
 Sex cells divide to produce gametes (sperm or egg).
 Gametes have half the # of chromosomes.
 Occurs only in gonads (testes or ovaries).
Male: spermatogenesis
Female: oogenesis
 Meiosis is similar to mitosis with some
chromosomal differences.
 Spermatogenesis
n=23
human
sex cell
sperm
n=23
n=23

2n=46
haploid (n)

n=23
diploid (2n) n=23

n=23

meiosis I meiosis II
Meiosis – mouse testes
Parent cell

1st division

2nd division

4 gametes
 Interphase I
 Similar to mitosis interphase.

 Chromosomes replicate (S phase).

 Each duplicated chromosome consist of two

identical sister chromatids attached at their
centromeres.

 Centriole pairs also replicate.

 Interphase I
 Nucleus and nucleolus visible.

chromatin
nuclear
membrane

cell membrane

nucleolus
 Meiosis I (four phases)
 Cell division that reduces the chromosome number
by one-half.
 four phases:
a. prophase I
b. metaphase I
c. anaphase I
d. telophase I
 Prophase I
 Longest and most complex phase (90%).
 Chromosomes condense.
 Synapsis occurs: homologous chromosomes come
together to form a tetrad.
 Tetrad is two chromosomes or four chromatids
(sister and nonsister chromatids).
 Prophase I - Synapsis
Homologous chromosomes

sister chromatids Tetrad

sister chromatids
 Homologous Chromosomes
 Pair of chromosomes (maternal and paternal) that are
similar in shape and size.
 Homologous pairs (tetrads) carry genes controlling the same
inherited traits.
 Each locus (position of a gene) is in the same position on
homologues.
 Humans have 23 pairs of homologous chromosomes.

a. 22 pairs of autosomes
b. 01 pair of sex chromosomes
 Karyotype
 A method of organizing the chromosomes of a cell in
relation to number, size, and type.
Homologous Chromosomes

eye color eye color

locus locus

hair color hair color

locus locus

Paternal Maternal
 Humans have 23 Sets of Homologous Chromosomes
Each Homologous set is made up of 2 Homologues.

Homologue

Homologue
 Autosomes
(The Autosomes code for most of the offspring’s traits)

In Humans the
“Autosomes”
are sets 1 - 22
21 trisomy – Downs Syndrome

Can you see the

extra 21st
chromosome?

Is this person
male or female?
 Sex Chromosomes
The Sex Chromosomes code for the sex of the offspring.
** If the offspring has two “X” chromosomes it will be a female.
** If the offspring has one “X” chromosome and one “Y” chromosome it will be a
male.

In Humans the “Sex

Chromosomes” are the
23rd set

XX chromosome - female XY chromosome - male

Boy or Girl? The Y Chromosome “Decides”

Y chromosome
X chromosome
 Crossing Over

 Crossing over (variation) may occur between

nonsister chromatids at the chiasmata.
 Crossing over: segments of nonsister chromatids
break and reattach to the other chromatid.
 Chiasmata (chiasma) are the sites of crossing over.
 Crossing Over - variation
nonsister chromatids Tetrad

chiasmata: site of variation

crossing over
 Another Way Meiosis Makes Lots of
Different Sex Cells – Crossing-Over

Crossing-over multiplies the already huge number of

different gamete types produced by independent
 Sex Chromosomes

XX chromosome - female XY chromosome - male

Prophase I

spindle fiber
centrioles

aster
fibers
 Metaphase I
 Shortest phase
 Tetrads align on the metaphase plate.
 INDEPENDENT ASSORTMENT OCCURS:
1. Orientation of homologous pair to poles is random.
2. Variation
3. Formula: 2n
Example: 2n = 4
then n = 2
thus 22 = 4 combinations
Metaphase I

OR

metaphase plate metaphase plate

 Anaphase I
 Homologous chromosomes separate and move
towards the poles.
 Sister chromatids remain attached at their
centromeres.
Anaphase I
 Telophase I

 Each pole now has haploid set of chromosomes.

 Cytokinesis occurs and two haploid daughter

cells are formed.
Telophase I
 Meiosis II
 No interphase II
(or very short - no more DNA replication)
 Remember: Meiosis II is similar to mitosis
 Prophase II
 same as prophase in mitosis
 Metaphase II
 same as metaphase in mitosis

metaphase plate metaphase plate

 Anaphase II
 same as anaphase in mitosis
 sister chromatids separate
 Telophase II

 Same as telophase in mitosis.

 Nuclei form.
 Cytokinesis occurs.
 Remember: four haploid daughter cells
produced.

gametes = sperm or egg

Telophase II
 Meiosis
n=2

sex cell sperm

n=2
n=2

2n=4
haploid (n)

n=2
diploid (2n) n=2

n=2

meiosis I meiosis II
 Variation
 Important to population as the raw material for
natural selection.

 Question:
What are the three sexual sources of
genetic variation?
 Fertilization

 The fusion of a sperm and egg to form a zygote.

 A zygote is a fertilized egg

sperm
n=23 n=23
egg
2n=46
zygote