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Cell Cycle
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FLOW OF DISCUSSION
1.Overview of the cell cycle
a. G1phase
b. S phase Interphase
c. G2 phase
d. Mitosis phase
• prophase, metaphase, anaphase, telophase, * cytokinesis
•  Meiosis
2.Intracellular Control of the Cell Cycle
a. Positive: Cyclin- dependent kinase & Cyclins
b. Negative: Rb & p53
3. Extracellular Control of the Cell Cycle
a. Mitogens
b. Growth factors
c. Survival factors
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Definition

 A cell cycle is a series of events that a cell passes through from the time until it
reproduces its replica.

 It is the growth and division of single cell into daughter cells and duplication
(replication).

 In prokaryotic cells, the cell cycle occurs via a process termed binary fission.

 In eukaryotic cells, the cell cycle can be divided in two periods

 a) interphase
 b) mitosis
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PHASES OF CELL CYCLE
 It consists of 2 major activities.
 INTER PHASE
 G1 (pre-synthetic phase)
 S (DNA synthesis)
 G2 (pre-mitotic phase)

 CELL DIVISION (MITOTIC PHASE)

a) Interphase- During this phase the cell grows, accumulating nutrients needed for
mitosis and duplicating its DNA.

b) Mitosis (M)-phase- During which the cell splits itself into two distinct cells.

 The duration of the cell cycle varies from hours to years. A typical human cell has
duration of 90h.
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Intracellular control of the cell cycle

 The cell cycle is controlled by regulator molecules that either:

 Promote the process (positive)
 Stop it from progressing (negative)
 z Positive: Cdks & Cyclins

 Cyclins

 The regulatory subunits of the protein kinases

that control the cell cycle

 Cyclin-Dependent Kinases (Cdks)

 The catalytic subunits of the protein kinases

 ◦ Must be associated with a cyclin in order to be

activated
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Negative: Rb & p53

 Tumor suppressor genes

 Tumor suppressor gene codes for a signaling protein in an inhibitory pathway.

 If a tumor suppressor gene mutates, the end result can be active cell division.
 Negative:
z Rb & p53

 Retinoblastoma protein(Rb)
 Prevents cell moving into S phase by binding to a transcription factor
 When Rb is phosphorylated it cannot bind so cell can move into S
phase

 p53
 prevents damaged from dividing (by inhibiting Rb pathway)
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Retinoblastoma protein (Rb)
 Rb halts the cell cycle by binding E2F. Rb releases its hold on E2F in response to cell
growth to advance the cell cycle.
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p53

 p53 protein halts cell division if it detects damaged DNA

 options:
 Stimulates repair enzymes to fix DNA
 Forces cell into G0 resting stage
 keeps cell in G1 arrest
 Causes apoptosis of damaged cell

 ALL cancers have to shut down p53 activity

 Cancer is essentially a failure of cell division control

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EXTRACELLULAR CONTROL OF THE CELL

 Mitogens
 stimulate cell division (PDGF)

 Growth factors
 stimulate cell growth

 Survival Factors
 inhibit apoptosis
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GROWTH FACTORS

 A signal transduction through phosphatidyl inositol

pathway

 Kinase cascade leads to increased translation

 Some factors stimulate both growth and cell cycle

progression
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SURVIVAL FACTOR

 MYOSTATIN

 These are inhibitory factors that inhibit the proliferation of myoblast that fuse to form
skeletal muscle cells.

 Myostatin Mutants decrease apoptosis in muscle tissue

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Interphase
 It is the longest phase. In a typical human cell, out of the 90h, interphase lasts for 89h.

 CHARACTERS OF INTERPHASE:

 It is the resting phase of the cell.

 But, the cells in the interphase are metabolically active.

 The cell grows during phase.

 During this phase mRNA and rRNA are synthesized.

 The chromosomes duplicates into two chromatids.

 The centrioles duplicates into two.

 The centrospheres of centrioles, microtubules arise. These microtubules form asters.

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G1 PHASE
 It is the first phase within the interphase.

 This period starts immediately after division. The daughter cells grow and increase in size
during this phase.

 It is a longer phase. It lasts for even years. The nerve cells remain permanently in G1 phase.
Generally, this stage lasts for 25 to 50% of the total interphase.

 During this phase 20 amino acids are formed, from which millions of proteins and enzymes are
formed, which are required in S phase. During this phase mRNA, rRNA and tRNAs are formed.
During this phase new cell organelles are formed.

 Concentration of cyclin D increases, resulting in phosphorylation and activation of necessary

transcription proteins resulting in synthesis of DNA polymerase DHFR etc which is required for
DNA replication.

 Formation of cyclin E complex is necessary for the transition from G1 to S phase (check point 1
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G0 PHASE
 It is the resting phase.

 In these cells cyclin D is in decreased concentration.

 Rb protein is in hypo-phosphorylated (active form).

 Hence, holds the cell cycle at check point 1 by inhibiting the expression of several
transcription proteins(E2F) that codes cyclins A and E necessary for cycle
progression.

 Growth factor stimulation takes the G0 cells to G1 phase.

 In interphase the cell prepares itself to cycle. The term post-mitotic is sometimes
used to refer both quiescent and senescent cells.

 Non-proliferative cells in eukaryotes generally enter the quiescent Go state from G1

and may remain quiescent for longer period of time or indefinitely
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DNA DAMAGE CHECKPOINTS

 These sense DNA damage both before the cell enters S phase (a G1 checkpoint) as
well as after S phase (a G2 checkpoint).

 Damage to DNA before the cell enters S phase inhibits the action of Cdk2 thus
stopping the progression of the cell cycle until the damage can be repaired.

 If the damage is so severe, that it cannot be repaired, then the cell destructs by
apoptosis.

 Damage (UV radiation, oxidative stress, etc) to DNA after S phase (the G2 checkpoint)
inhibits the action of Cdk1 thus preventing the cell from proceeding from G2 to mitosis.

 In the S phase if DNA replication stops at any point on the DNA, the progress through
the cell cycle is halted until the problem is solved.
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S Phase

 Cyclin E/cdk and cyclin A/cdk regulate the processes in phase S.

 By phosphorylating and activating proteins and enzymes that are involved in DNA
synthesis.

 During this phase DNA synthesis occurs. The DNA molecule duplicates. All the
chromosomes have been replicated. This period lasts for 35 to 40% of interphase.

 During this phase, synthesis is completed as quickly as possible due to the exposed
base pairs may be destroyed by the external proteins (drugs) or any mutagens (such as
nicotine).

 Microtubule formation and chromatin remodeling occurs in this phase

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G2 Phase

 Pre-mitotic phase.

 It is a period of rapid cell growth and protein synthesis which the cell ready itself for
mitosis.

 The nucleus increases in volume. Metabolic activities essential for cell division, occur
during this phase. mRNA, tRNA and rRNA synthesis also occur.

 This phase has double the number of chromosomes.

 All the other cellular components are duplicated for the 2 daughter cells.

 Cyclin A/cdk and cyclin B/cdk complexes are active which are necessary for the cell to
enter into M phase (check point 2).
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M Phase (Mitosis)

 G2 cells are divided into two daughter cells which may enter the cycle again at G1
phase or come out of the cycle to G0 phase.

 Mitosis is the distribution of the two sets of chromosomes into two separate and equal
nuclei.

 This is the division phase. During this phase the cell divides. This phase has a short
duration.

 A typical human cell cycle has duration of 90h. Of these the M phase has duration of
45 to 60min.
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M Phase (Mitosis)

 This phase has two sub-phases called karyokinesis and cytokinesis.

 Karyokinesis refers to the cell division of nucleus into two daughter nuclei. It has 4
sub-stages, namely prophase, metaphase, anaphase and telophase.

 Cytokinesis refers to the cell division of the cytoplasm resulting in two daughter
cells.
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M Phase (Mitosis)

 PROPHASE

 Chromatin condenses.

 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

 Nuclear envelope disintegrates

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M Phase (Mitosis)

 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

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M Phase (Mitosis)

 METAPHASE

 Chromosomes align on an axis called the metaphase plate

 The spindle consists of microtubules, one attached to each

chromosome
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M Phase (Mitosis)

 ANAPHASE

 Each centromere splits making two chromatids free

 Each chromatid moves toward a pole

 Cell begins to elongate, caused by microtubules not associated with the kinetochore
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M Phase (Mitosis)

 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 by a contractile ring of actin and myosin

filaments and pinches the cell inwards

What are the result of mitosis?

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SIGNIFICANCE OF MITOSIS

 Permits growth and repair.

 In plants it retains the ability to divide throughout the life of the plant

 In mammals, mitosis is necessary: Fertilized egg becomes an embryo

 Embryo becomes a fetus

 Allows a cut to heal or a broken bone to mend

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MEIOSIS

 Formation of Gametes (Eggs & Sperm)

 Called Reduction- division

 Preceded by interphase which includes chromosome replication

 Two meiotic divisions

 Meiosis I and Meiosis II

 Original cell is diploid (2n)

 Four daughter cells produced that are haploid (n)

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SIGNIFICANCE OF MEIOSIS
 Two haploid (1n) gametes are brought together through fertilization to form a
diploid (2n) zygote

 Meiosis must reduce the chromosome number by half • Fertilization then restores
the 2n number
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MEIOSIS I: PROPHASE I

 Prophase I is further subdivided into periods known as

 Leptotena
 Zygotena
 Pachytena
 Diplotena
 Diakinesis
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PROPHASE I
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METAPHASE I
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ANAPHASE I
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Telophase I
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MEIOSIS II: PROPHASE II
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MEIOSIS II: METAPHASE II
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MEIOSIS II: ANAPHASE II
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MEIOSIS II: TELOPHASE II
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RESULTS OF MEIOSIS
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SUMMARY OF MEIOSIS I
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SUMMARY OF MEIOSIS II
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COMPARISON OF DIVISIONS