Apoptosis - Definition
A pathway of cell death induced by a tightly
regulated suicidal program, in which the cells
destined to die activate enzymes that degrade
cells own nuclear DNA and nuclear,
Significance of apoptosis
• During development → many cells produced
in excess → programmed cell death →
contribute to sculpturing of organs & tissues.
• In human body about one lakh cells are
produced every second by mitosis and a
similar number die by apoptosis.
Programmed cell death is as
needed for proper normal
development as mitosis is.
• Formation of fingers & toes of
fetus requires removal by
• Sloughing off of endometrium at
the start of menstruation.
Apoptosis in physiologic situations
Programmed destruction during embryogenesis
Involution of hormone dependent tissues
Cell loss in proliferating cell populations
Elimination of harmful self- reactive lymphocytes
Death of host cells
STAGES OF CLASSIC APOPTOSIS
DEATH SIGNAL / STIMULI (extrinsic or intrinsic)
Commitment to die (reversible)
Dead cell (condensed, crosslinked)
ENGULFMENT (macrophages, neighboring cells)
Initiation of apoptosis by activation of
signalling pathways :
There are two main signalling pathways in apoptosis :
(A) Extrinsic/death receptor-initiated pathway :
Round oval mass of intensely eosinophilic cytoplasm
Fragmented nuclei with condensed chromatin
• Release of mitochondrial pro-apoptotic
proteins tightly controlled by BCL2 family of
• Antiapoptotic proteins : BCL2, BCLXL & MCL1
• Proapoptotic proteins : BAX and BAK
• BCL2 sensor proteins : BAD, BIM, BID, Puma, Noxa
(also called BH3 proteins)
• Also, cytoplasm of normal cells contains
inhibitors of apoptosis (IAP) which are
neutralized by proapoptotic factors.
Apoptosis: Role in Disease
TOO MUCH: Tissue atrophy
TOO LITTLE: Hyperplasia
→Neurons are post-mitotic.
→Neuronal death caused by loss of proper
connections, loss of proper growth factors (e.g.
NGF), and/or damage (especially oxidative
→Neuronal dysfunction or damage results in loss of
synapses or loss of cell bodies (synaptosis, can be
reversible; apoptosis, irreversible)
→HUNTINGTON'S DISEASE etc.
Apoptosis eliminates damaged cells
(damage => mutations => cancer)
Tumor suppressor p53 controls senescence and
apoptosis responses to damage.
Most cancer cells are defective in apoptotic
response(damaged, mutant cells survive)
High levels of anti-apoptotic proteins
Low levels of pro-apoptotic proteins ===>
VIRUS ASSOCIATED CANCER
• Human papilloma viruses (HPV)
•causes cervical cancer
•produces a protein (E6)-binds & inactivates apoptosis promoter p53.
• Epstein-Barr Virus (EBV)
- cause of mononucleosis and a/w some lymphomas
–produces a protein similar to Bcl-2
–produces another protein that causes the cell to
increase its own production of Bcl-2. Both these actions
make the cell more resistant to apoptosis (thus enabling
a cancer cell to continue to proliferate).
• Some B-cell leukemia and lymphomas express high
levels of Bcl-2 → block apoptotic signals. The high
levels result from a translocation of BCL-2 gene into
an enhancer region for antibody production.
• Melanoma cells avoid apoptosis by inhibiting
expression of the gene encoding Apaf-1.