DIVISION OF EUKARYOTIC CELLS

MITOSIS
’Wole Akinola, Ph.D.
 Cell Division: Overview
Cell division
• Is required for growth, reproduction and replacement of
dead cells
• Occurs rapidly in cells of intestinal epithelium and
epidermis; but slowly in the thyroid gland and pancreas.
• Does not occur in neurons and skeletal and cardiac muscle
cells, which are terminally differentiated.
• Is enhanced by hormones such as somatotropin,
progesterone and thyroid hormones; and growth factors
such as epithelial growth factor (see below).
• Is inhibited in normal cells by chalones. Besides, substances
such as colchicine (and its derivatives: colcemide,
podophyllin, and podophyllotoxin), vinblastine and
vincristine, as well as exposure to ionizing radiation, impair
cell division
 Types of Cell Division
Cell division may take the form of:
i. Mitosis, which occurs in somatic cells
ii. Meiosis, which occurs in germ cells; and
iii. Amitosis, which is almost restricted to
pathological cases
 Mitosis
Mitosis is the division of the nucleus and cytoplasm of a cell
that results in the formation of two daughter cells
Mitosis
• Is required for growth and replacement of dead cells in an
organism
• Is preceded by the interphase stage, when nuclear DNA
quantity is doubled (at the S phase of the cell cycle).
• Involves two main processes: karyokinesis (division of the
nucleus), and cytokinesis (division of the cytoplasm).
Karyokinesis splits the nucleus into two nuclei; while
cytokinesis splits the cytoplasm.
• Occurs in four phases: prophase, metaphase, anaphase and
telophase. Mitosis takes 1–2 hours.
• Results in the production of two daughter cells that are
genetically identical to each other and to the parent cell
 Interphase Stage of Cell Cycle
• Interphase is the phase between two successive
mitoses.
• During interphase:
– The cell prepares for prophase of cell division
– DNA replication (doubling of nuclear DNA quantity)
occurs.
• Each chromosome thus consists of two sister chromatids,
joined at the centromere.
– Chromatin exists as euchromatin and
heterochromatin as chromosomes are not yet visible.
– The nucleolus is still observable; while the centrioles
are duplicated (at S phase), and tubulin is synthesized.
Prophase of Mitosis
The prophase of mitosis is
characterised by:
• Progressive shortening and
coiling of chromatin to form
chromosomes.
– 46 chromosomes are seen in the
human nucleus at prophase.
– Each has two parallel chromatids
joined at the centromere.
• Positioning of the two pairs of
centrioles at opposite poles of
the cell.
– A pair of centrioles was
duplicated at interphase to
produce two pairs.
• Formation of mitotic Prophase of Mitosis
spindle and asters from
microtubules.
– The spindle and asters are
collectively called
amphiaster.
– Tubulin required for
formation of the spindle is
synthesized at G2 phase of
interphase
• Disintegration of the
nucleolus and
disappearance of the
nuclear envelope.
– These mark the end of
prophase.
Prophase
 Metaphase
of Mitosis
During metaphase of mitosis,
• Chromosomes align at the
equatorial plate of the cell.
– Microtubules of mitotic spindle are
involved in the arrangement of
chromosomes at the equatorial
plate.
– Microtubules are seen to attach to
the centromere of chromosomes.
• Karyotyping can be done as the
chromosomes are displayed at the
equatorial plate of the cell. In
karyotyping, microtubules are
destroyed by colchicine to
immobilize the chromosomes,
which can then be observed
microscopically.
Prometaphase
&
Metaphase
 Chromosomes
in metaphase
• TEM of a sectioned
metaphase cell shows
several features of the
mitotic apparatus,
including the very
electron-dense
chromosomes bound at
their kinetochores
(arrows) to
microtubules of the
spindle.
• The microtubules are
seen to converge on the
centrosomes, in each of
which centriole-like
structures are found.
 Anaphase
of Mitosis
During anaphase of mitosis,
• Centromere of each
chromosome splits along
its longitudinal axis to
separate the sister
chromatids from each
other.
• Spindle microtubules
shorten actively, thereby
pulling the chromatids
towards opposite poles of
the cell.
– Thus, two groups of 46
chromatids are ultimately
constituted within the cell.
Anaphase
 Telophase
of mitosis
During telophase of
mitosis,
• Chromosomes begin to
uncoil and extend
– as they revert to
chromatin form
• Nucleolus is
reconstituted; while
nuclear membrane is
formed around each
daughter nucleus
• Cytokinesis (division of
the cytoplasm) is
proceeding gradually.
Telophase
Cytokinesis:
Division of the Cytoplasm
During cytokinesis,
• A cleavage furrow (a constriction of the cell)
is formed between the two emerging
nuclear groups.
– This furrow is produced by actin and myosin
filaments that accumulate beneath the cell
membrane at the equatorial plate.
• Mitotic spindle begins to disintegrate and
the cell eventually separates into two
identical daughter cells.
– Thus,Organelles of the dividing cell are
shared between the two daughter cells.
Through mitosis,
• Over 100 billion cells are replaced each day
• The epidermis and digestive tract replace
their dead cells rapidly.
Cytokinesis
 • Cell cycle consists of a series of events that
occurs during the lifespan of a cell.

Cell Cycle

• It includes
– mitosis, characterised by the physical events that lead to cell multiplication,
and
– interphase stage, which precedes mitosis. Interphase stage includes G1, S, and
G2 phases.
 G1 phase of the cell cycle
• Active growth and
RNA and protein
synthesis occur
during the G1
phase (presynthetic
phase).
• G1 phase succeeds
mitosis and lasts for
about 25 hrs in
bone tissue.
 S phase of the cell cycle
• Synthetic phase (S
phase) follows G1 phase
• Synthetic phase is
xrised by DNA
replication,
– the chromosomes
double their DNA
proportion (but
chromosome number
remains diploid).
• Duplication of
centrioles also begins at
this stage.
• S phase lasts for about
8 hrs.
• During the G2 phase (post-DNA
duplication phase), the cell
prepares to enter mitosis. G2 phase of the
• G2 phase lasts for about 3 hrs.
• It is characterised by synthesis of cell cycle
tubulin (from which spindle
microtubules are formed); and
synthesis of non-histone
proteins.
• Repair of some damaged DNA
also occurs at the G2 phase
– in addition to that which occurs
at the G1 phase
• This phase is also characterised
by accumulation of the
maturation promoting factor
(MPF).
– This protein triggers the onset of
mitosis, the condensation of the
chromosomes and the
disintegration of nuclear
envelope.
 Mitotic phase of the cell cycle
• Mitosis follows the
G2 phase; and it
proceeds in four
stages.
– prophase
– metaphase
– anaphase
– telophase
• Mitosis lasts for 1-2
hrs.
GO phase of the cell cycle
• Certain cells enter the
GO phase.
• This is characterised by
temporal or permanent
suspension of activities
relating to mitosis,
– as occurs in highly
differentiated cells such
as neurons, skeletal
muscle cells and cardiac
muscle cells.
 Control of the cell cycle
• One factor that determine the
time a cell spends in G1 is its
state of differentiation, or how
much time it spends expressing
gene products specific to its cell
type before resuming DNA
replication.
• Differentiating cells in growing
tissues may have very long G1
periods and such cells are often
said to be "in a G0 phase" of the
cell cycle.
– From this phase many
differentiated cells can return to
the cycle, but some stay in G0 for
a long time or even for their
entire lifetime.
• Entry into each phase of the cell Control of the
cycle is controlled by proteins called
cyclins and cyclin-dependent
kinases which
cell cycle
phosphorylate/activate many
proteins needed for phase-specific
functions.
• Cyclin activity produces an important
restriction point (R) late in G1 and a
similar G2/M checkpoint which are
important for the maintenance of
chromosome stability and cell
viability.
– These control points stop the cycle
under conditions unfavorable to the
cell and help insure that neither the
DNA replication nor the mitotic phases
occurs prematurely.
– e.g., at the G2/M checkpoint the cell
pauses while enzymes insure that all
DNA has been replicated properly
 Control of the cell cycle
• Cycling in postmitotic cells (bypassing the G0 state) is
triggered by signals from the extracellular environment
– Such signals include mitogens or growth factors, which
activate cell surface receptors.
• Nutrients and proteins needed for DNA replication
accumulate and when all is ready (at the restriction
point) DNA synthesis begins.
• Entry or progression through each phase of the cell
cycle is under the control of specific sets of proteins:
cyclins and cyclin-dependent kinases (CDKs)
– Kinases phosphorylate proteins
– In this way diverse cellular activities are coordinated at
specific phases of the cell cycle
 Promoters of mitosis
• Mitotic cell division is enhanced by growth
factors such as
– fibroblast growth factor,
– nerve growth factor,
– erythropoietin (precursor of erythrocyte growth
factor),
– epithelial growth factor,
– Insulin, and
– Insulin-like growth factor, etc.
 Clinical correlates of mitosis
• Normally, cell division is under the control of a group of
genes called proto-oncogenes.
– Mutation of proto-oncogenes could result in malignancy.
• Cancer could arise from exposure to:
– ionizing radiation,
– viral infections, and
– certain chemical substances capable of altering the
expression of proto-oncogenes.
• Increased number of mitotic figures is seen in
malignant tumor.
• Ionizing radiation damages DNA, and could thus inhibit
mitosis. A feature of radiation sickness is the failure of
epithelia to replace lost cells
– with resultant ulceration of the skin and mucosa.
 Clinical correlates of mitosis
• Neoplasm (tumor) is an abnormal mass of tissue formed by
uncoordinated cell division. It could be benign or
malignant.
• Benign tumor is characterised by slow growth and non-
invasiveness;
– malignant tumor (cancer) has capacity for rapid growth and
invasion of other tissues.
• Growth factors such as fibroblast growth factor and
erythropoietin enhance cell division.
– These proteins are needed in small amounts.
• Proto-oncogenes are a group of genes that control the cell
cycle.
– Mutation of these genes (e.g. following exposure to certain viral
infections, radiation and some chemicals) could result in cancer
 Clinical correlates of mitosis
• Some growth factors are being used in medicine.
– One example is erythropoietin, which stimulates proliferation,
differentiation, and survival of red blood cell precursors in the bone
marrow.
• Progression through the cell cycle is also regulated by various
signals which halt cycling under adverse conditions.
– DNA damage can arrest the cell cycle not only at the G1 restriction
point, but also during S or at a checkpoint in G2.
– G1 arrest may permit repair of the damage to occur before the cell
enters S phase, so that the damaged DNA is not replicated.
• If the problem encountered at any checkpoint cannot be corrected
while cycling is halted, tumor suppressor genes or proteins (such as
p53) are activated and the cell's activity is redirected toward
apoptotic cell death.
– The gene encoding p53 is often mutated in cancer cells, thus reducing
the cell's ability to detect and repair damaged DNA.
• Inheritance of damaged DNA by daughter cells results in a greater
frequency of mutations and general instability of the genome,
which may contribute to the development of cancer.
 Clinical correlates of mitosis
• Rapidly dividing cells tissues (e.g, intestinal epithelial cells) frequently
contain cells in mitosis, whereas slowly growing tissues do not.
• The increased number of mitotic figures and abnormal mitoses in tumors
are important characteristics that distinguish rapidly growing malignant
tumors from benign tumors.
• Cell proliferation and differentiation are controlled by a group of genes
called proto-oncogenes;
– altering the structure or expression of these genes promotes the production
of tumors.
• Proto-oncogenes can be changed into oncogenes by a mutation in their
DNA sequences or by DNA translocations that move genes to active
promoter sites causing them to be inappropriately or permanently
expressed.
• Altered proto-oncogenes have been associated with several tumors and
hematologic cancers.
– Proto-oncogenes encode almost any protein involved in the control of mitotic
activity, including various specific growth factors, the receptors for growth
factors, and various kinases and other proteins involved in intracellular
signaling of growth factors.
– There is a growing list of such proto-oncogenes.
 Clinical correlates of mitosis
• Various cancer-causing factors (e.g, some chemical
substances, certain types of radiation, and certain viral
infections) can induce DNA damage or mutations
– which can lead to abnormal cell proliferation that bypasses
normal regulation mechanisms for controlled growth and
results in the formation of tumors
• The term tumor is now usually used as a synonym for
neoplasm
• Neoplasm can be defined as an abnormal mass of
tissue formed by uncoordinated cell proliferation.
• Neoplasms are either benign or malignant according to
their characteristics of slow growth and no
invasiveness (benign) or rapid growth and great
capacity to invade other tissues (malignant)
• Cancer is the common term for all malignant tumors