MOLECULAR BASIS OF

APOPTOSIS
INTRODUCTION
A form of programmed and coordinated cell death that
occurs in multicellular organism
Causes- physiological and pathological causes
MECHANISM
1.INITIATION OF APOPTOSIS

Withdrawal of normal cell survival signals

• Eg. Absence of certain hormones (endometrial shedding, regression
of breast after pregnancy) , growth factors , cytokines.

Agents of cell injury

Eg. Heat , radiation , hypoxia , toxins , free radicals.

2. INITIATION OF DEATH-SIGNALLING
PATHWAYS

After self destruct mode has been initiated, cell death signaling mechanisms are
initiated by activation if caspases by one of the two pathways
1. Extrinsic/cell death receptor initiated pathway
2. Intrinsic/ mitochondrial pathway

However, finally mediators of cell death are activated caspases.

 INTRINSIC PATHWAY
This pathway is due to increased mitochondrial permeability and is a major
mechanism.
Release of cytochrome C protein from mitochondria from cytoplasm of cell initiates
this cell into apoptosis
It is regulated by members of anti-apoptotic , pro-apoptotic & a third BCL family of
oncogene. ( B cell lymphoma )

Antiapoptotic BCL family

• These proteins lie on outer surface of mitochondria,ER & cell membrane
• These proteins don’t permit leakage of mitochondrial protein to cytosol
Proapoptotic BCL family
• Promote mitochondrial leakage of cytochrome C protein into cytosol
EXTRINSIC PATHWAY
 activated by death receptors on cell membrane
An important cell death receptor is type-1 tumour necrosis factor ( TNF1 )
& related transmembrane protein called Fas (CD95) and ligand(FasL)
ACTIVATION OF INITIATOR
CASPASES
In Intrinsic pathway:

Mitochondrial protein cytochrome c is liberated

into cytosol and binds with another protein , This complex binds to precursor caspases – 9
apoptosis activating factor (APAF-1) and forms and cleaves them to form activated proteins
complex called apoptosomes.

This process is regulated by certain physiological inhibitors which block activation of

caspases.
IN EXTRINSIC PATHWAY:

FADD which is formed after receptor-

The activation of caspases-10
ligand interaction binds to inactive
caspases-8 can be inhibited by FLIP
caspases-10 and cleaves it to form its
(FLICE inhibitory protein)
active form caspases-8
4. ACTIVATION OF APOPTOSIS
EXECUTING CASPASES
Both mechanisms lead to activation of cascade of caspases, eventually converging
to active form of caspases-3 & caspases-6 .
These executional caspases ( 3&6 ) act on various components of cell and leads to :
chromatin clumping , cytoskeletal damage , disruption of ER ,
mitochondrial damage , disturbed cell membrane
5. REMOVAL OF DEAD CELLS
Dead apoptotic cells have certain protein on their surface , which facilitate recognition and
engulfment by macrophages
1. Phosphatidylserine molecule :
which is generally present inside the cell membrane , is exposed outside during
apoptosis which facilitates recognition of apoptotic cells by macrophage receptor.
2. thrombospondin:
few apoptotic bodies are coated with thrombospondin which is a adhesive glycoprotein
molecule this helps recognition of apoptotic cells by macrophage receptor.
3. Antibodies :
some apoptotic bodies are coated with natural antibodies , which are recognised by
receptors on macrophages.
PHAGOCYTOSIS
Apoptosis is followedby phagocytosis.
Phagocytosis in apoptosis is unaccompanied by inflammation.
REFERENCES:
Harsh mohan & google .