4. 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, cytoplasmic proteins
9. WHY APOPTOSIS?
To eliminate cells that :
• are potentially harmful
• have outlived their usefulness / aged
• are damaged beyond repair
10. Since it is genetically regulated , apoptosis is sometimes
referred to as programmed cell death.
Certain forms of necrosis , called “ necroptosis” are also
genetically programmed, but by a distinct cell of genes.
16. CASPASES
• ‘c’ - cysteine protease(an enzyme with cysteine in its
active site)
‘aspase’- ability of these enzyme to cleave after aspartic
acid residues
More than 10 members
Their catalytical activity depends on a critical cysteine-residue within
a highly conserved active-site pentapeptide
Central executioners of cell death
17. Depending on order in which they are activated during
apoptosis, they are divided into
• Initiator caspase - 8, 9
• Executioner caspase -3, 6,7
Presence of cleaved,active caspases is a marker for cells
undergoing apoptosis
18.
19.
20.
21. EXECUTION PHASE
Final phase of apoptosis
Mediated by proteolytic cascade
After initiator caspases ( 2, 8, 9 and 10) are cleaved to generate its
active form, the enzymatic death program is set in motion by rapid
sequential activation of the executioner caspases – 3,6
Caspase -3 activates DNase which causes degradation of
chromosomal DNA within the nuclei and causes chromatin
condensation.
Caspase -3 induces cytoskeletal reorganisation and disintegration
of cell into apoptotic bodies.
23. APOPTOSIS-ROLE IN DISEASE
Pathological condition arise as a result of
dyregulation in apoptosis
defective apoptosis with increase cell survival
OR
Increased apoptosis with increased cell death
24.
25. AUTOIMMUNE DISEASES
T-cells mature in thymus, but before they can enter
the blood stream they are tested to ensure that they
are effective against foreign antigen and are also not
reactive against normal healthy cells.
Any ineffective or self reactive T-cells are removed
through induction of apoptosis.
26. Poor regulation of apoptosis in T- lymphocyte results
Autoimmune Diseases of cytotoxic T lymphocytes.
Eg : Behcet’s Disease, Ankylosing Spondylitis
Poor regulation of apoptosis in B –cell
Eg : SLE , Scleroderma , Multiple sclerosis
RHEUMATOID ARTHRITIS : excessive proliferation of synovial
cells is thought to be due in part to the resistance of these cells
to apoptosis.
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME [ALPS]:
mutation in FAS gene
27. CANCER AND APOPTOSIS
Apoptosis eliminates damaged cells (damage => mutations => cancer)
Apoptosis is regulated by two major genes p53 & Bcl-2.
Tumor suppressor p53 controls senescence and apoptosis
responses to damage.
Mutations or overexpression of these genes will result in Cancer.
Most cancer cells are defective in apoptotic response (damaged,
mutant cells survive)
High levels of anti-apoptotic proteins
or
Low levels of pro-apoptotic proteins ===> CANCER
28. Virus associated cancer
Several human papilloma viruses (HPV) have been implicated in
causing cervical cancer. One of them produces a protein (E6) that
binds and inactivates the apoptosis promoter p53.
•Epstein-Barr Virus (EBV), the cause of mononucleosis and
associated with 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).
29. Radiation and chemicals used in cancer therapy induce apoptosis
in some types of cancer cells.
induced apoptosis in stomach carcinoma cell
Before induction 24h after induction 48h after induction
30. APOPTOSIS AND HIV
Human Immunodeficiency Virus infects CD4+ T cells
and HIV Tat protein increases the expression of Fas
receptor, resulting in excessive apoptosis of T cells.
Hallmark- the decline in the number of the patient's
CD4+ T cells (normally about 1000 per microliter (μl)
of blood).
31. NEURODEGENERATIVE DISEASES
Apoptosis of hippocampal neuron+ Overexpression
of BCL-2 Alzheimer’s D/s
Apoptosis of neurons in striatum which control body
movements Huntington’s Disease
Apoptosis of lower motor neurons –Amyotrophic
Lateral Sclerosis
In stroke -activation of glutamate receptors which
act as a trigger to stimulate apoptosis
