CELL CYCLE

AND ITS
REGULATION
 Cell division is the
process by which
a parent cell divides
into two or
more daughter cells
Prokaryotic Cell Division
• Bacterial cells reproduce by
Binary Fission.
• Much simpler process than in
eukaryotes.
• Begins with DNA replication.
• Followed by elongation of cell,
and formation of a septum
between the two halves.
• Results in two cells that are
identical (clones) of original
cells.
 Eukaryotic Cell Division
Two forms
• MITOSIS
• Leaves the daughter cell capable of
dividing again
• Produces diploid cells
• MEIOSIS
• Cell is permanently transformed into
a gamete and cannot divide again
until fertilization
• Produces haploid gametes
 EUKARYOTIC CELL
DIVISION IS A SMALL
SEGMENT OF A
LARGER CELL CYCLE
IT IS A HIGHLY
CONTROLLED
SEQUENCE OF EVENTS
THAT LEADS TO DNA
REPLICATION AND CELL
DIVISION
 Maintains tissue
homeostasis

Regulates physiological
growth processes
(regeneration and repair)
There are four main
components of the cell
cycle:

PHASES
CHECKPOINTS
CYCLINS / CDKs Regulate
the
ROLE OF GENES cell cycle
PHASES
CHECKPOINTS
CYCLINS / CDKs
ROLE OF GENES
PHASES of the Cell Cycle
• G0 / Gap 0 / Resting Phase
• Inter - Phase
• G1 / Gap 1 / pre-synthetic
• S / Synthetic
• G2 / Gap 2 / pre-mitotic
• M / Mitotic Phase
• Prophase
• Metaphase
• Anaphase
• Telophase
• Cytokinesis
Cells can enter the G1 phase either
from G0 phase or the M phase

Stable cells which are Labile cells which are

quiescent but can continuously dividing,
undergo multiplication in replacing those that are
response to appropriate destroyed. Some
stimuli. Some examples examples are:
are: - epithelia of skin, oral
- Parenchymal cells of cavity, vagina & cervix
liver, kidney and - Lining mucosa of all
pancreas excretory ducts of glands
- Fibroblasts and smooth of the body
muscle cells - Lining epithelium of GI
- Vascular endothelial and GU tract
cells - Cells of bone marrow
- Lymphocytes and other and hematopoietic
leukocytes tissue
Stable/Quiescent cell
go through this
transition from G0 to
G1 phase, the first
decision sep, which
functions as
GATEWAY TO THE
CELL CYCLE.
Another kind are the non-
dividing tissues which
have left the cell cycle
and cannot undergo
division in post-natal life.
To this group belong
neurons and cardiac
muscle cells.
M - Mitosis phase.  Cell divides forming 2 daughter
cells.
PROPHASE
• PROMETAPHASE
• METAPHASE
• ANAPHASE
• TELOPHASE
CYTOKINESIS • Cytoplasmic Division
• Usually occurs between
late anaphase and end of
telophase
• Two mechanisms
• Cell plate formation
(plants)
• Cleavage (animals)
Mitosis/Cytokinesis outcome
• 1 parent cell  2 identical
daughter cells
• Chromosome number remains
the same from one generation
to the next
 PHASES

CHECKPOINTS
CYCLINS / CDKs
ROLE OF GENES
CHECKPOINTS of the
CELL CYCLE
• Each cell cycle phase is
dependent on the proper activation
and completion of the previous
phase.

• Checkpoints prevent cell cycle

progression at specific points,
allowing verification of necessary
phase processes and repair
of DNA damage.

• There are three checkpoints:

• G1 /S (Restriction) Checkpoint
• G2 /M Checkpoint
 key decision of whether the
cell should
- divide
- delay division
- or enter a resting stage
This point is the RATE
LIMITING STEP FOR
REPLICATION
Because after this point
G1 (Restriction) Checkpoint cells are irreversibly
commited to DNA replication
 Checks the DNA
after replication and
monitors:
- If cell can safely
undergo mitosis
- cell should
undergo DNA
repair
G2 Checkpoint - cell should
underdo apoptosis
• METAPHASE

Metaphase Checkpoint
- AKA Spindle Checkpoint
- The cell ensures that all
chromosomes are attached
to the spindle
The spindle checkpoint:
-the signal for anaphase to proceed is
transmitted through anaphase-promoting
complex (APC)
-APC activates the proteins that remove the
cohesin holding sister chromatids together
 PHASES
CHECKPOINTS

CYCLINS / CDKs
ROLE OF GENES
 REGULATION OF CELL CYCLE

The orderly progression of cells

through the various phases of cell
cycle is orchestrated by
- Cyclins
- cyclin-dependent kinases( CDKs)
- and their inhibitors.
The Cyclins are so called because of
the cyclic nature of their production
and degradation.

The cell cycle may be seen as a

“relay race” in which each lap is
regulated by a distinct set of
cyclins – as one set leaves the
track, the next set takes over !!!
 The cyclin dependent kinases, in
contrast to the cyclins, are expressed
constitutively during the cell cycle in
an “inactive” form and acquire
catalytic activity by binding to and
forming “complexes” with the cyclins.

Activated cyclin dependent kinases in

these complexes drive the cell cycle
by “phosphorylating” proteins that are
critical for cell cycle transitions.
 As cyclins “arouse” the CDKs,
CYCLIN DEPENDENT KINASE
INHIBITORS(CDKIs) “silence” the
CDKs.

Thus the CDKIs exert a negative

control over the cell cycle.
Cyclins, CDKs & CDKIs
in the CELL CYCLE
• More than 15 cyclins
have been identified.
• Cyclins D, E, A and
B appear
sequentially during
the cell cycle.
• CDKs 4,6,2,1 appear sequentially
and form complexes as:
• CDK4 – cyclin D
• CDK6 – cyclin D
• CDK2 – cyclin E
• CDK2 – cyclin A
• CDK1 – cyclin A
• CDK1 – cyclin B
Complexes cycD-CDK4,
cycD-CDK6 & cycE-CDK2
regulate G1-S transition by
phophorylating RB protein.
Growth signals in the form of growth factors like
PDGF, FGF etc.

Transient and limited activation of the growth

factor receptors.

Transduction of the growth signal across the

cytosol.

Induction and activation of nuclear regulatory

factors.

Activation of CYCLIN D
 CYCLIN D binds to CDK 4,6

This complex phosphorylates RB gene

E2F transcription factor is released

Activation of CYCLIN E

CYCLIN E binds to CDK 2

This complex leads to initation of DNA synthesis

Complexes cycA-CDK2 &
cycA-CDK1 are active in the
S - Phase.
Complex cycB-CDK1 is
essential for the G2-M
transition.
 A protien phosphatase :
E2F transcription factor
“Cdc-25”
(released from RB)
Activates CYCLIN B
Also activates CYCLIN A

Complexes with Complexes with

CDK – 2 & 1 CDK - 1

These complexes of cyclin A & B regulate

critical events at the G2M transition phase like:
Decrease in microtubule stability
The separation of centrosomes
Chromosome condensation
 Cyclins, CDKs & CDKIs
in the CELL CYCLE

• CDKIs have two families:

• CIP/WAF family: inhibits CDKs broadly

• p21
• p27
• p57

• INK4 family: selective inhibitor of cyclinD-CDK4

• p15 and cyclinD-CDK6
• p16
• p18
• p19
• p14ARF
CIP/WAF family inhibits
The CDKs broadly.
INK4 family inhibits
cycD-CDK4 & cycD-CDK6.
 p14ARF

inhibits

MDM – 2

Thus prevents
the degradation
Degrades the of p53
p53 gene
 PHASES
CHECKPOINTS
CYCLINS / CDKs

ROLE OF GENES
 ROLE of RB gene in the
REGULATION of CELL CYCLE
The RB gene and its product RB protein
play a key role in the regulation of the
cell cycle.
Its importance lies in the enforcement of
G1 phase.
G1 phase is a decision making phase in
which the cells can continue to divide,
enter quiescence or senescence.
RB is a key node in this decision making
process.
RB exists in an
active hypo-phosphorylated
state in the quiescent cell and an
inactive hyper-phosphorylated
state during the G1/S transition.

The
active hypo-phosphorylated
form of RB blocks the cell cycle
hence called a
“tumour suppressor gene”
The hypo-phosphorylated
active form of RB blocks
the transition from
G1 to S phase by two
methods:
• Sequesters the E2F
family of transcription
factors.
• Recruits chromatin
remodeling protiens :
histone deacetylase and
methyltransferase which
modify cromatin so as to
make promoters
insensitive to
transcription factors.
 Mitogenic signaling and
growth factors lead to
Cyclin D expression and
activation of CycD-CDK4,6
complexes.

These complexes
“phosphorylate” RB thus
inactivating it.

E2F is released which

further activates:
• Cyclin E
• DNA polymerases
• Thymidine kinases
• DHF reductase

These collectively
stimulate DNA replication
and progression of the cell
cycle.

RB is again de-phosphorylated during the M-Phase

 If RB gene is absent as a result of gene
mutations or its ability to regulate the
E2F transcription factors is derailed,
The molecular breaks on the cell cycle are
released and the cell moves through the
cell cycle.
 The emerging
paradigm is that the
loss of normal cell
cycle control is
central to malignant
transformation and
that at least one of
the four key
regulators of the cell
cycle:
• CDKI – p16(INK4a)
• Cyclin D
• CDK 4
• RB
Are dysregulated in
VIRTUALLY ALL
HUMAN CANCERS !!
 ROLE of p53 gene in the
REGULATION of CELL CYCLE
The gene TP53 is located on the short arm of
chromosome 17. Its protein product is called “p53”.

Over 50% of human tumours have mutated p53.

The three leading causes of cancer death:

LUNG, COLON & BREAST carcinomas
have mutated/inactive p53.

Patients with inherited mutations of p53 are said to

have Li-Fraumeni syndrome and have a 25-fold
chance of developing a malignancy by the age of
50 years.
 It is known as the
“GATE-KEEPER”
against the formation of cancer.

Acts as a
“MOLECULAR POLICEMAN”
that prevents the propagation
of genetically damaged cells
 Apart from the inherited and somatic mutations, p53
function can be inactivated by other mechanisms
like:
 E6 protein of Human pappiloma virus(HPV) can
bind to and degrade p53.
 Mutations in MDM2 & MDMX which stimulate the
degradation of p53.

IN NONSTRESSED HEALTHY CELLS, P53 HAS A SHORT HALF

LIFE OF 20 MINS BECAUSE OF ITS ASSOCIATION WITH
MDM2 WHICH TARGETS FOR ITS DESTRUCION,
BUT IN STRESSED CELLS, P53 UNDERGOES POST-
TRANSLATIONAL MODIFICATION TO BE UNAFFECTED BY
MDM2 – BUT HERE IF MDM IS MUTATED, IT IS
OVEREXPRESSED AND DEGRADES P53.
 p53 THWARTS THE NEOPLASTIC
TRANSFORMATION BY THREE
MECHANISMS

Temporary permanent programmed

cell cycle cell cycle cell death
arrest arrest

QUIESCENCE SENESCENCE APOPTOSIS

DNA damged by
ionizing radiations,
carcinogens and
mutagens.
The manner in which
p53 senses DNA
damage is by two
protein kinases:
- ATM(ataxia telangiectasia mutated)
- ATR(ataxia telangiectasia & RAD3)
Both of them
phosporylate p53 and
DNA – Repair proteins.
 Activated p53

Transcription of CDK-
inhibitor p21

P21 inhibits cyclin-CDK

complexes &
phosphorylation of RB

Cell cycle arrested at

G1
 Activated p53

Also induces growth

arrest and DNA damge
protein(GADD45)

Helps in DNA repair

 Activated p53

Also induces growth

arrest and DNA damge
protein(GADD45)

If repaired successfully

P53 upregulates MDM2

Leading to its own

destruction

Releasing the cell cycle

block.
 Activated p53

If repair fails

P53 upregulates the

pro-apoptotic gene
BAX

Leading to APOPTOSIS
However repression of
a subset of pro-
proliferative & anti-
apoptotic genes is the
key to p53 response.

P53 does this via

mi-RNAs(mir-34 family)
These mi-RNAs either
inhibit the growth
promoting genes like
cyclins

thus lead to quiescence

or senescence
or they inhibit the anti-
apoptotic genes like
BCL-2

thus lead to Apoptosis

 If p53 is defective

The cell marches into a

one way street leading
to malignant
transformation.

Thus p53 has rightfully

been called a
GUARDIAN
OF THE
GENOME
GENETIC
BASIS OF
CANCER
Four classes of normal regulatory
genes:
1. the growth-promoting proto-oncogenes
2. the growth-inhibiting tumor suppressor
genes
3. genes that regulate programmed cell
death (apoptosis)
4. genes involved in DNA repair
are the principal targets of genetic
damage.
THE GROWTH-PROMOTING
PROTO-ONCOGENES

They act the following 5

levels:

Growth signals in the form of growth factors

activation of the growth factor receptors.

Transduction of signal across cytosol.

activation of nuclear regulatory factors.

Entry and progression of cell into cell cycle

THE GROWTH-PROMOTING
PROTO-ONCOGENES

mutations convert proto-

oncogenes into constitutively
active cellular oncogenes that are
involved in tumor development
because the oncoproteins they
encode endow the cell with self-
sufficiency in growth
THE GROWTH-PROMOTING
PROTO-ONCOGENES

GROWTH FACTORS
PDGF-β SIS (official Overexpress Astrocytoma
chain name ion Osteosarco
PBGFB) ma
Fibroblast HST1 Overexpress Stomach
growth ion cancer
factors INT2 (official Amplification Bladder
name FGF3) cancer
Breast
cancer
Melanoma
TGF-α TGFA Overexpress Astrocytoma
ion s
Hepatocellul
ar
carcinomas
HGF HGF Overexpress Thyroid
ion cancer
THE GROWTH-PROMOTING
PROTO-ONCOGENES
GROWTH FACTOR RECEPTORS
EGF-receptor ERBB1 Overexpressi Squamous
family (EGFR), on cell carcinoma
ERRB2 of lung,
gliomas
FMS-like FLT3 Amplification Breast and
tyrosine ovarian
kinase 3 cancers
Receptor for RET Point mutation Leukemia
neurotrophic
factors
    Point mutation MEN 2A and
B, familial
medullary
thyroid
carcinomas

PDGF PDGFRB Overexpressi Gliomas,

receptor on, leukemias
translocation
Receptor for KIT Point mutation GIST,
stem cell seminomas,
(steel) factor leukemias
THE GROWTH-PROMOTING
PROTO-ONCOGENES

PROTEINS INVOLVED IN SIGNAL TRANSDUCTION

GTP- KRAS Point mutation Colon, lung,
binding and
pancreatic
tumors
HRAS Point mutation Bladder and
kidney
tumors
NRAS Point mutation Melanomas

Nonreceptor ABL Translocation CLL

tyrosine
kinase
ALL
RAS signal BRAF Point mutation Melanomas
transduction
WNT signal β-catenin Point mutation HCC
transduction
THE GROWTH-PROMOTING
PROTO-ONCOGENES
NUCLEAR-REGULATORY PROTEINS
Transcriptio C-MYC Translocation Burkitt
nal lymphoma
activators N-MYC Amplification Neuroblastoma,
small-cell
carcinoma of
lung
L-MYC Amplification Small-cell
carcinoma of
lung
CELL CYCLE REGULATORS
Cyclins Cyclin D Translocation Mantle cell
lymphoma
Amplification Breast and
esophageal
cancers
Cyclin E Over Breast cancer
expression
Cyclin- CDK4 Amplification Glioblastoma,
dependent melanoma,
kinase sarcoma
 THE GROWTH-INHIBITING
TUMOR SUPPRESSOR GENES

Failure of growth inhibition is one of

the fundamental alterations in the
process of carcinogenesis.
Whereas oncogenes drive the
proliferation of cells, the products
of tumor suppressor genes apply
brakes to cell proliferation
 Subcellular Gene Function Somatic Inherited
Locations Mutations Mutations
Cell surface TGF-β Growth Carcinomas Unknown
receptor inhibition of colon
E-cadherin Cell Carcinoma of Familial
adhesion stomach gastric
cancer
Inner aspect of plasma NF1 Inhibition of RAS signal Neuroblastomas Neurofibromatosis type 1 and
membrane transduction and of p21 cell sarcomas
cycle inhibitor
Cytoskeleton NF2 Cytoskeletal stability Schwannomas and meningiomas Neurofibromastosis type 2,
acoustic schwannomas, and
meningiomas
Cytosol APC/β-catenin Inhibition of signal Carcinomas of stomach, colon, Familial adenomatous polyposis
transduction pancreas; melanoma coli/colon cancer
PTEN PI3 kinase signal transduction Endometrial and prostate cancers Cowden syndrome
SMAD2 and SMAD4 TGF-β signal transduction Colon, pancreas tumors Unknown
Nucleus RB1 Regulation of cell cycle Retinoblastoma; osteosarcoma Retinoblastomas, osteosarcoma
carcinomas of breast, colon, lung
p53 Cell cycle arrest and Most human cancers Li-Fraumeni syndrome; multiple
apoptosis in response to DNA carcinomas and sarcomas
damage
WT1 Nuclear transcription Wilms' tumor Wilms' tumor
P16/INK4a Regulation of cell cycle by Pancreatic, breast, and Malignant melanoma
inhibition of cyclindependent esophageal cancers
kinases
BRCA1 and BRCA2 DNA repair Unknown Carcinomas of female breast
and ovary; carcinomas of male
breast
 Subcellular Gene Function Somatic Inherited
Locations Mutations Mutations
Cell surface TGF-β receptor Growth inhibition Carcinomas of colon Unknown
E-cadherin Cell adhesion Carcinoma of stomach Familial gastric cancer

Inner aspect NF1 Inhibition of RAS Neuroblasto Neurofibrom

of plasma signal transduction mas atosis type 1
membrane and of p21 cell and
cycle inhibitor sarcomas
Cytoskeleton NF2 Cytoskeletal stability Schwannomas and Neurofibromastosis type 2,
meningiomas acoustic schwannomas, and
meningiomas
Cytosol APC/β-catenin Inhibition of signal transduction Carcinomas of stomach, colon, Familial adenomatous polyposis
pancreas; melanoma coli/colon cancer
PTEN PI3 kinase signal transduction Endometrial and prostate Cowden syndrome
cancers
SMAD2 and TGF-β signal transduction Colon, pancreas tumors Unknown
SMAD4
Nucleus RB1 Regulation of cell cycle Retinoblastoma; osteosarcoma Retinoblastomas, osteosarcoma
carcinomas of breast, colon,
lung
p53 Cell cycle arrest and apoptosis in response to Most human cancers Li-Fraumeni syndrome; multiple
DNA damage carcinomas and sarcomas
WT1 Nuclear transcription Wilms' tumor Wilms' tumor
P16/INK4a Regulation of cell cycle by inhibition of Pancreatic, breast, and Malignant melanoma
cyclindependent kinases esophageal cancers
BRCA1 and DNA repair Unknown Carcinomas of female breast
BRCA2 and ovary; carcinomas of male
breast
 Subcellular Gene Function Somatic Inherited
Locations Mutations Mutations
Cell surface TGF-β receptor Growth inhibition Carcinomas of colon Unknown

E-cadherin Cell adhesion Carcinoma of stomach Familial gastric cancer

Inner aspect of plasma NF1 Inhibition of RAS signal Neuroblastomas Neurofibromatosis type 1 and
membrane transduction and of p21 cell sarcomas
cycle inhibitor

CytoskeletonNF2 Cytoskeletal Schwannomas NF type 2,

stability and acoustic
meningiomas schwannomas
and
meningiomas
Cytosol APC/β-catenin Inhibition of signal transduction Carcinomas of stomach, colon, Familial adenomatous polyposis
pancreas; melanoma coli/colon cancer
PTEN PI3 kinase signal transduction Endometrial and prostate cancers Cowden syndrome
SMAD2 and SMAD4 TGF-β signal transduction Colon, pancreas tumors Unknown
Nucleus RB1 Regulation of cell cycle Retinoblastoma; osteosarcoma Retinoblastomas, osteosarcoma
carcinomas of breast, colon, lung
p53 Cell cycle arrest and apoptosis Most human cancers Li-Fraumeni syndrome; multiple
in response to DNA damage carcinomas and sarcomas
WT1 Nuclear transcription Wilms' tumor Wilms' tumor

P16/INK4a Regulation of cell cycle by Pancreatic, breast, and esophageal Malignant melanoma
inhibition of cyclindependent cancers
kinases
BRCA1 and BRCA2 DNA repair Unknown Carcinomas of female breast and
ovary; carcinomas of male breast
 Subcellular Gene Function Somatic Inherited
Locations Mutations Mutations
Cell surface TGF-β receptor Growth inhibition Carcinomas of colon Unknown
E-cadherin Cell adhesion Carcinoma of stomach Familial gastric cancer
Inner aspect of plasma NF1 Inhibition of RAS signal transduction and Neuroblastomas Neurofibromatosis type 1 and
membrane of p21 cell cycle inhibitor sarcomas
Cytoskeleton NF2 Cytoskeletal stability Schwannomas and Neurofibromastosis type 2, acoustic
meningiomas schwannomas, and meningiomas

Cytosol APC/β- Inhibition of Carcinomas Familial

catenin signal of stomach, adenomatous
transduction colon, polyposis
pancreas; coli/colon
melanoma cancer
PTEN PI3 kinase signal Endometrial Cowden
transduction and prostate syndrome
cancers
SMAD2 TGF-β signal Colon, Unknown
and transduction pancreas
SMAD4 tumors
Nucleus RB1 Regulation of cell cycle Retinoblastoma; osteosarcoma Retinoblastomas, osteosarcoma
carcinomas of breast, colon,
lung
p53 Cell cycle arrest and apoptosis in response Most human cancers Li-Fraumeni syndrome; multiple
to DNA damage carcinomas and sarcomas
WT1 Nuclear transcription Wilms' tumor Wilms' tumor
P16/INK4a Regulation of cell cycle by inhibition of Pancreatic, breast, and Malignant melanoma
cyclindependent kinases esophageal cancers
BRCA1 and BRCA2 DNA repair Unknown Carcinomas of female breast and
ovary; carcinomas of male breast
 Subcellular Gene Function Somatic Mutations Inherited
Locations Mutations
Cell surface TGF-β receptor Growth inhibition Carcinomas of colon Unknown
E-cadherin Cell adhesion Carcinoma of stomach Familial gastric cancer
Inner aspect of plasma NF1 Inhibition of RAS signal transduction Neuroblastomas Neurofibromatosis type 1 and
membrane and of p21 cell cycle inhibitor sarcomas
Cytoskeleton NF2 Cytoskeletal stability Schwannomas and meningiomas Neurofibromastosis type 2,
acoustic schwannomas, and
meningiomas
Cytosol APC/β-catenin Inhibition of signal transduction Carcinomas of stomach, colon, pancreas; Familial adenomatous polyposis
melanoma coli/colon cancer
PTEN PI3 kinase signal transduction Endometrial and prostate cancers Cowden syndrome
SMAD2 and TGF-β signal transduction Colon, pancreas tumors Unknown
SMAD4

Nucleus RB1 Regulation of Retinoblastoma; Retinoblasto

cell cycle osteosarcoma mas,
carcinomas of osteosarcom
breast, colon, a
lung
p53 Cell cycle Most human Li-Fraumeni
arrest and cancers syndrome;
apoptosis in multiple
response to carcinomas
DNA damage and
sarcomas
WT1 Nuclear transcription Wilms' tumor Wilms' tumor
P16/INK4a Regulation of cell cycle by inhibition Pancreatic, breast, and esophageal Malignant melanoma
of cyclindependent kinases cancers
BRCA1 and DNA repair Unknown Carcinomas of female breast
BRCA2 and ovary; carcinomas of male
breast
 Subcellular Gene Function Somatic Inherited
Locations Mutations Mutations
Cell surface TGF-β receptor Growth inhibition Carcinomas of colon Unknown
E-cadherin Cell adhesion Carcinoma of stomach Familial gastric cancer
Inner aspect of plasma NF1 Inhibition of RAS signal transduction Neuroblastomas Neurofibromatosis type 1 and
membrane and of p21 cell cycle inhibitor sarcomas
Cytoskeleton NF2 Cytoskeletal stability Schwannomas and Neurofibromastosis type 2,
meningiomas acoustic schwannomas, and
meningiomas
Cytosol APC/β-catenin Inhibition of signal transduction Carcinomas of stomach, colon, Familial adenomatous polyposis
pancreas; melanoma coli/colon cancer
PTEN PI3 kinase signal transduction Endometrial and prostate Cowden syndrome
cancers
SMAD2 and SMAD4 TGF-β signal transduction Colon, pancreas tumors Unknown

Nucleus
RB1 Regulation of cell cycle Retinoblastoma; osteosarcoma Retinoblastomas, osteosarcoma
carcinomas of breast, colon,
lung
p53 Cell cycle arrest and apoptosis in Most human cancers Li-Fraumeni syndrome; multiple
response to DNA damage carcinomas and sarcomas

WT1 Nuclear Wilms' tumor Wilms' tumor

transcription
P16/INK4a Regulation of cell Pancreatic, Malignant
cycle by inhibition breast, and melanoma
of esophageal
cyclindependent cancers
kinases
BRCA1 DNA repair Unknown Carcinomas of
and female breast
BRCA2 and ovary;
carcinomas of
male breast
 GENES THAT
REGULATE
APOPTOSIS

Apoptosis represents a
barrier that must be
surmounted for cancer to
occur.
The sequence of events
that lead to apoptosis are
by signaling through the
death receptor CD95/Fas
(extrinsic pathway) and by
DNA damage (intrinsic
pathway).
SITES AT WHICH APOPTOSIS IS
FRUSTRATED BY CANCER
CELLS ARE:

Reduced levels of
Fas-CD95 may
render the tumour
cells less susceptible
to apoptosis
SITES AT WHICH APOPTOSIS IS
FRUSTRATED BY CANCER
CELLS ARE:

Increased levels of a
protien FLIP may bind
to and inactivate the
death induced
signalling compex
thus preventing the
activation of
CASPASE 8.
SITES AT WHICH APOPTOSIS IS
FRUSTRATED BY CANCER
CELLS ARE:

Over-expression of
BCL-2(anti-apoptotic)
leading to decreased
efflux of
cytochrome C.

Found in 85% of B-
cell lymphomas of the
follicular type.
SITES AT WHICH APOPTOSIS IS
FRUSTRATED BY CANCER
CELLS ARE:

Reduced levels of
pro-apoptotic BAX
resulting from loss of
p53.
SITES AT WHICH APOPTOSIS IS
FRUSTRATED BY CANCER
CELLS ARE:

Loss of APAF-1 and

upregulation of
inhibitors of apoptosis
 GENES THAT REGULATE
DNA REPAIR
DNA repair genes themselves are not
oncogenic but their abnormalities
allow mutations in other genes during
the process of normal cell division.

There are three DNA repair systems:

• Mismatch Repair genes : HNPCC
• Nucleotide excision repair : Xeroderma
Pigmentosum
• Recombination repair genes: Ataxia Telangiectasia
Bloom Syndrome
Fanconi Anemia
 Thus we see that DNA mutations
disrupt the cell cycle.
While normal cells will stop dividing
if there is a mutation in the DNA,
cancer cells will continue to divide
with mutation.
CANCER IS A THUS A DISEASE
OF THE CELL CYCLE.
THANK
YOU