BS10003 | Science of Living Systems | 2 nd Jan 2023

Cell Biology of Development and Cancer

Arindam Mondal
School of Bio Science | Arindam.mondal@iitkgp.ac.in | 03222-284572
 Development of
Multicellular Organisms
Cycle of life depends on two modes of cell division

Mitosi
Fertilizatio s
n Zygote
(single
cell)

Sper Ovu Morula

m m (Multicellula
r)
Meiosi Mitosis and
s Differentiation

Adu Embry
lt o
Mitosis and
Morphogenesis
Expansion of Zygote (single cell ) to adult human (10 13 cells):
Mitosis cell division
The fundamental events in cell division cycle of any
living system:
Duplication of genetic material/information
(DNA) in the parent cell.
Accurate distribution (segregation) of identical
DNA into two cells of next generation
(progeny/daughter cells)
The duration of the cell division cycle vary from
organism to organism, and in a single organism it may
vary between cell types:
During early development i.e. embryonic stage,
cells divide once in 8 minutes.
The epithelial cells in the lining of our intestine
divide once in 1 day.
Liver cells divide in 1 year.
Most brain cells (neurons) don’t divide.
Key components of the machinery of cell division cycle:
Microtubules – One of the three major classes of the filaments of the
cytoskeleton. Tubulins are the monomeric units.
Kinetochores – Complex structure formed from proteins on a mitotic
chromosome to which microtubules are attached. Helps in the movement of
chromosomes to the poles.
Centrioles – Short cylindrical array of microtubules.
Contractile ring – Ring containing actin and myosin that contracts to pinch
the two daughter cells apart.
Stages of Mitosis
Mitosis cell division: equational division

Division of 1 parent cell produces 2 daughter cells

Chromosome number remains same after Mitosis
(2n to 2n)- equational division
Replication doubles the genomic content (2c to
4c), Mitosis halves it (4c to 2c)
Somatic cells are diploid (2n) andGametes
(sperm/ovum) are haploid (n)
Most higher eukaryotes are diploid (2n); i.e. their body (somatic)
cells contain two copies of the genome set
Their sex cells (gametes) are haploid (n) i.e. these cells contain one
copy of the genome set

Chromosomes
haploid 1 set
diploid 2 sets
triploid 3 sets
tetraploid 4 sets
hexaploid 6 sets
octaploid 8 sets
Diploid set of human chromosomes
How does the ‘2n’ genome arise in embryo?
Through fertilization of two sex cells (gametes): one basic
genome set (n) from male gamete (father’s sperm) and another set
(n) from female gamete (mother’s egg).

Sper Ovu
m n m
n (gametes)
X
fertilizatio
n

2n
(n
)
Embry
(n o
So, in order to keep chromosome number
) constant, gametes need to be haploid (n)

How do we get haploid gametes in a diploid organism?

Production of sex cells (gametes):
Meiosis cell division
Two rounds of division of 1 parent cell
produces 4 daughter cells
Chromosome number becomes half after
Meiosis; i.e. diploid (2n) cell divides to
generate haploid (n) gametes- reductional
division
Replication doubles the genomic content
(2c to 4c), Meiosis reduces it (4c to c)

Spermatogenesis Oogenesis
2 2
n n

n n Meiosis n n

n n n n n n n n
Ovum

Sperm
s
 Unique features of mitosis and meiosis compared
Meiosis: single round of
2n, 2C 2n, chromosome duplication
2C
followed by two rounds of
2n, 4C 2n, chromosome segregation.
4C
1st round (Meiosis-I)
segregates the homologs
that pair up.
2nd round (Meiosis-II)
segregates the sister-
chromatids
Mitosis: homologs do not
n, 2C 2n, 4C pair up and segregate
n, 2C
but the sister-chromatids
segregate

n, n, n, n, 2n,2C 2n,2C
Chromosome orientation in mitosis and meiosis
Mitosis: Separation of chromatids

Meiosis: Separation of homologous

chromosomes
 Mitosis vs Meiosis
Mitosis (equational division): Somatic (body) cells increase in number in this
mode
Meiosis (reduction division): Specialized diploid cells (meiocytes) undergo two
sequential nuclear divisions to form four haploid gametes (sperms and eggs in
plants, animals) or spores (fungi, algae).

 
 One copy of Genome (n) in each
The gametes of most higherSperm/Ovum
eukaryotes are haploid (n) i.e. these cells
contain one copy of the basic genome set (one set of chromosomes)

Somatic Cells Somatic Cells Gametes

(2n) (2n) (n)
Mitosi Meiosi
(22 x 2) + s s 22 + Eg
XX X g
2 F
n

Mitosi Meiosi 22 + Sper

(22 x 2) + s s X m
XY or Sper
22 + m
2 M
Y
 Diploid (2n) Genome arises during fertilization
Through fertilization of two haploid gametes, i.e., one genome set (n)
from male gamete (i.e. sperm) and another genome set (n) from female
gamete (i.e. egg).

Gamete formation (2n  Fertilization (n + n 

n) 2n)

Meiosi
s Egg: 22 +
X
(n) F
2 F 2
n n

Meiosi Sperm: 22 +
s X
(n)
Sperm: 22 +
2 M 2 M
Y
 Asymmetric cell division is essential to generate
different cell types in multicellular organisms
SC
N
Asymmetric B In multicellular organisms, stem cells can
division
&
give rise to two different cells, one that
Self Renewal of the resembles the parent cell and one that
Stem Cell SC IP does not. Such asymmetric cell division
generates all different cell types in the
body
Daughter cells produced by such
Symmetri asymmetric cell division may differ in size,
SC IP c shape, composition of protein/RNA and
division most crucially in gene expression which
confers different fates on the two cells
In symmetric cell division, the parental
SC IP cell gives rise to two daughter cells that
resemble each other, at least visually
Differentiating
cells

SC= stem cell NOTE: GENOMIC CONTENT IS SYMMETRICALLY

IP= intermediate progenitor SEGREGATED EVEN IN ASYMMETRIC DIVISION
How does asymmetric cell division
occur? Essential to asymmetric cell
division is polarization of the
parental cell and then
differential incorporation of
parts of the parental cell into
the two daughters
Some cytoplasmic components
(such as mRNA or proteins) are
localized in some part of the
cell
The unequal distribution of
these components to the
daughter cells results in
transcription of different sets of
genes
The resulting proteins
determine the cell-fate
Cell and Molecular
Biology of Cancer
Cell Division Cycle Alternates Between Mitosis (M)
and Interphase (G1, S, G2)
Interphase – long period between two
divisions during which cells grow, duplicate
chromosomes and prepare for division
G1 (Gap phase 1) – birth of cell to the
onset of chromosome duplication
S (Synthesis phase) – chromosome
duplication (formation of sister
chromatids) due to replication of DNA
G2 (Gap phase 2) – end of
chromosome duplication to the onset
of mitosis.

M: Mitosis phase – nuclear division follows division of cytoplasmic

content (cytokinesis) to separate sister chromatids into daughter cells
G0: resting phase – cells exit from cell cycle and survive for days or years
Cell cycle control system

The eukaryotic cell cycle

control system has
three major
checkpoints as
surveillance mechanism
for cell cycle progression
or transitions :
1. Start or restriction point
(between G1 and S)
2. G2/M checkpoint
3. Metaphase/anaphase
transition
 Cyclins & cyclin-dependent kinases (Cdks):
central components of the cell cycle control system

Central component of cell cycle control

system are cyclin-dependent kinases
(Cdks). Their activities rise and fall as the
cell progresses through its cycle. This
leads to cyclical changes in the
phosphorylation of proteins that initiate or
regulate major cell cycle events.
Cdk activity is primarily controlled by
Cyclin proteins. Cdks are active only
when they tightly bind cyclin.
The levels of cyclin proteins periodically
rise and fall which result in periodic
activation and deactivation of the Cdks.
 Different classes of cyclins undergo cyclical
synthesis and degradation

C
y
c
li
Three classes
n of cyclins are required in all Eukaryotic cells:
1.
c
G1/S-cyclins bind Cdks at the end of G1 and commit the cell to DNA replication.
o
2. S-cyclins
n bind Cdks during S phase and are required for the initiation of DNA replication.
3. M-cyclins
c promote the events of mitosis.
In most cells,
e a fourth class of cyclins, the G1-cyclins, helps promote passage through Start or
n
the restriction point in late G1.
t
r
a
ti
What happens when cell cycle regulation goes wrong?
Uncontrolled proliferation- TUMOUR
Cell division without checking for DNA damage-
1. DNA replication errors are not corrected
2. DNA damage due to external mutagens are not corrected
ACCUMULATION OF MUTATIONS IN
GENOME
Error rate of DNA Polymerase= 1 in 105 nucleotides
A human cell has 6 billion base pairs
So 1 round of replication of the human genome will make 120,000 errors!!!

How are those errors repaired?

During replication: DNA Polymerase has proofreading activity
After replication: A well designed DNA repair machinery repairs the damage

If the DNA damage is beyond repair, the cell dies by initiating Apoptosis
 What happens when DNA is damaged?
Replication Ionizing UV Mutagenic ROS Cigarette
errors Radiation exposure chemicals smoking

Cell cycle DNA repair Apoptosis (Programmed

pauses at programme Cell Death)
Checkpoint
 What is a mutation?
A mutation is an alteration in the nucleotide
sequence of the genome of an organism
Mutation in a gene results in alteration in
the protein product
Spontaneous mutations: due to replication
error
Induced mutations: caused by mutagens

Mutagen: a physical or chemical agent that changes the DNA sequence

Examples: radiation (UV, X ray etc.), tobacco, chemical agents
Carcinogen: a substance or agent that promotes carcinogenesis or cancer
formation
Examples: Asbestos, tobacco smoke, aflatoxin, arsenic, radiation, food
colors, certain viruses etc.
 Germline mutations vs Somatic Mutations
Spermatogenesi Oogenesi
s s
Germlin
e
mutation Zygot
e
Mutation Somatic
in gamete mutation
genome Ovum

Sper fertilizatio
ms n

Somatic
mutation

Zygot
e
Mutation transmitted to Mutation may lead to
progeny Cancer
 What causes cancer?- Gene Mutations

A. Tumor Suppressor Genes: A. Proto-oncogenes:

Products are involved in
Cell cycle regulation
DNA repair
Cell death
Loss-of-function mutation
leads to uncontrolled cell
division
Products are involved in
Growth regulation
Regulation of cell
division
Cellular communication
Cell death
Gain-of-function mutation
converts them to
Oncogenes, which leads to
uncontrolled cell division

About One Percent of the Genes in the Human Genome Are

Cancer-Critical
 p
Role of tumour suppressor gene GUARDIAN
5
p53 OF
THE GENOME
3

Normal cell DNA damage – rise in P53 level: DNA damage and p53 absent-
division does not (i) cell cycle arrest for DNA repair (i) no cell cycle arrest
depend on p53 and
protein or
(ii) Induction of cell death (ii) no apoptosis
the cell continues to divide with
DNA damage/genetic
abnormality
Cancer is a multistep process: in
each step accumulating mutations
and altering cells properties
 Hallmarks of Cancer Cells

Uncontrolled mitotic division- TUMORIGENESIS

Evasion of cell death signals- IMMORTALIZATION

Induce formation of blood vessels- ANGIOGENESIS

Invade healthy tissue- METASTASIS

 1. Development of Tumor

Hallmarks of
Cancer
 2. Angiogenesis: Formation of blood
vessels in tumour

Hallmarks of
Cancer
Normal angiogenesis
Tumour-induced angiogenesis
 3. Immortalization:
Evading Apoptosis

Dividing Dividing
cell cell
DNA DNA
Damage Damage
Hallmarks of
Cancer High No
p53 p53
Cell cycle No cell cycle
arrest arrest
Uncontrolled
o cell division
r
DNA damage Induction of
repaired Apoptosis

Normal cell (If DNA damage is No DNA No

division beyond repair) damage Apoptosi
repair s

Daughter
cells Tumo
ur
 4. Metastasis: Invasion and tumor formation at a new site

Hallmarks of
Cancer
Various modalities of cancer
treatment
Books