Apoptosis by Yatendra Singh

1. APOPTOSIS
Yatendra Singh
Asst. Professor
Faculty of Pharmaceutical Sciences
Rama University, Kanpur
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2. 18_02_four_phases.jpgEUKARYOTIC CELL CYCLE

4. APOPTOSIS refers to an energy dependent, asynchronous,
genetically controlled process by which single cell self destructs
when apoptosis genes are activated.
Cell shrink and detach from neighbouring cells ,and nucleus broke
down.
Nuclear fragment and organells condense and packed into
vesicles exocytosed and ingested by surrounding cell.
APOPTOSIS
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5. MORPHOLOGICAL FEATURES:
Involvement of single cell.
Shrunken masses.
Show pyknosis and karyorrehexis.
Projections on cell membrane.
Formation of apoptotic body.
BIOCHEMICAL CHANGES:
Proteolysis.
Protein – protein cross-linking.
Appearance of phosphatidylserine on outer membrane of cell
membrane.
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6. STAGES OF CLASSIC APOPTOSIS
Healthy cell
DEATH SIGNAL (extrinsic or intrinsic)
Commitment to die (reversible)
EXECUTION (irreversible)
Dead cell (condensed, crosslinked)
ENGULFMENT (macrophages, neighboring cells)
DEGRADATION
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7. MOLECULAR MECHANISM
Initiators
Extrinsic Intrinsic
Two pathways
Extracellular Interacellular
Two phases
Decision phase
Involvement of two gene:
BCL-2
p-53
Execution phase
caspases
Death receptor Mitochondria
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8. Bcl-2
 Family of proteins that includes promoters and inhibitors
 Proto-oncogene
 Localized to outer mitochondrial membrane
 Can form homo & heterodimers
 Exhibits biphasic expression
 Promoters- BaX, BaD, BiD, BaK
 Inhibitors- Bcl-2, Bcl-XL
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9. CASPASES
 Proteins which degrade other proteins are employed by
apoptosis - Caspases
 Made as inactive precursors - Procaspases
 These are activated by other proteins when the right
signal is received.
 One caspase cleaves the lamin proteins resulting in the
irreversible breakdown of the nuclear membrane.
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10. 18_21_proteolytic_cas.jpg
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11. DEATH RECEPTOR PATHWAY
DEATH RECEPTOR + LIGAND
CONFORMATIONAL CHANGES IN INTERACELLULAR DOMAIN OF
RECEPTOR WHICH IS DEATH DOMAIN
RECRUITMENT OF VARIOUS PROTEIN
FORMATION OF DISC (DEATH INDUCING SIGNAL
COMPLEX)(= PROTEIN +RECEPTOR COMPLEX)
RECRUITMENT OF CASPASES 8,3,6 AND VARIOUS PROTEINS
APOPTOSIS
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12. MITOCHONDRIAL PATHWAY
CELL STRESS, FREE RADICAL STIMULATION
RELEASE OF PROAPOPTOTIC PROTEINS –BCL-2
RELOCATION OF PROTEIN TO CELL MEMBRANE
INTERACTION BETWEEN PROAPOPTOTIC AND ANTIAPOPTOTIC PROTEIN
FORMATION OF PT PORE (PERMEABILITY TRANSITION PORE),
RELEASE OF Cyt C
RELEASE OF APOPTOSOME (Cyt C + Apaf +PROCASPASES 9)
RECRUITMENT OF PROCASPASES 9
RELEASE OF PROCASPASES 3
APOPTOSIS
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13. Extrinsic Death Signaling Pathway
Intrinsic Death Signaling Pathway
DR4/DR5
TRAIL
Trimerization
DD
FADD
DED
Autocatalytic
activation intitiator
procasp-8 or-10
DISC
Activation of
effector
casp-3, -6, -7
APOPTOSIS
Substrate cleavage
DNA fragmentation
Bax/Bak
Apaf-1
Procasp-9
Apoptosome
Bcl-2/
Bcl-XL
Casp-9 activation
Cytochrome c
TWO
PATHWAYS OF
APOPTOSIS
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14. CLINICAL RELEVANCE OF APOPTOSIS
Central nervous system :Alzheimer’s disease
Cardiovascular system
Autoimmune disease : Rheumatic arthritis
Viral infection
Sepsis and multi-organ dysfunction
Placental development
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