Chết tế bào có chương trình

TS.BS. Đoàn Thị Kim Phượng

phuongdk75@gmail.com
Chết tế bào do tổn thương
- Tổn thương cơ học
- Phơi nhiễm với chất độc hại
Chết tế bào tự nguyện
- Các tín hiệu nội sinh
- Các tín hiệu ngoại sinh
Chết tb có chương trình liên quan chặt chẽ tới sự
phân hủy protein, đứt gẫy ADN của tế bào. Sau
đó các sản phẩm này đc các tế bào khác nhanh
chóng thực bào.
Là một phần cần thiết trong cuộc sống của mọi
sinh vật đa bào

Đóng vai trò chính từ khi phát triển phôi cho đến
khi chết.
Apoptosis cần cho sự phát triển phôi thai

– Đứt đuôi nòng nọc

– Sự hình thành cấu tạo các ngón chân, ngón tay của thai nhi

Apoptosis cần để phá hủy tế bào

Examples:
– Tế bào bị nhiễm vius
– Tế bào của hệ thống miễn dịch
– Tế bào có ADN tổn thương
– Tế bào ung thư
Chết TB có chương trình vs.
Chết TB tổn thương
Chết TB tổn thương Chết Tb có chương trình
• TB sưng to • TB kết đặc
• Vỡ màng • Màng còn nguyên vẹn
• ATP bị suy yếu • Yêu cầu ATP
• TB ly giải, đáp ứng với • Tb bị thực bào, không có
phản Ứng viêm phản ứng mô
• DNA đứt gẫy ngẫu nhiên • DNA đứt gẫy từng vạch
hoặc nhòe • Trong cơ thể, các tb đơn lẻ
• Trong cơ thể, toàn bộ bị ảnh hưởng
vùng mô bị ảnh hưởng
NECROSIS Vs APOPTOSIS

Wilde, 1999
STAGES OF APOPTOSIS

Induction of apoptosis related genes, signal transduction

Sherman et al., 1997

 APOPTOSIS: Morphology

organelle
reduction
membrane
blebbing &
changes
cell
mitochondrial
leakage shrinkage

nuclear chromatin
fragmentation condensation

Hacker., 2000
 APOPTOSIS: Morphological events
cell shrinkage
organelle reduction
mitochondrial leakage
chromatin condensation
nuclear fragmentation
membrane blebbing & changes
Blebbing & Apoptotic bodies
The control retained over the cell
Bleb membrane & cytoskeleton allows intact
pieces of the cell to separate for
recognition & phagocytosis by Ms

Apoptotic body

M M
What makes a cell decide to commit suicide?

Withdrawal of positive signals

examples :
– growth factors for neurons
– Interleukin-2 (IL-2)

Receipt of negative signals

examples :
– increased levels of oxidants within the cell
– damage to DNA by oxidants
– death activators :
• Tumor necrosis factor alpha (TNF-)
• Lymphotoxin (TNF-β)
• Fas ligand (FasL)
 Caenorhabditis elegans
1090 cells 131 cells apoptosis

decision engulfment degradation

to die execution

ced-3 ced-1
ced-4 nuc-1
ced-2
ced-5
ced-6
egl-1 ced-9
ced-7
ced-10
ces-2 ces-1
 Apoptosis: Pathways
“Extrinsic Pathway”

Death Death Initiator

Ligands Receptors Caspase 8

Effector
“Intrinsic Pathway”
Caspase 3 PCD

DNA da Initiator
mage Mitochondria/
& p53 Cytochrome C Caspase 9
 MAJOR PLAYERS IN
APOPTOSIS

• Caspases
• Adaptor proteins
• TNF & TNFR family
• Bcl-2 family
 Ligand-induced cell death
Ligand Receptor
FasL Fas (CD95)
TNF TNF-R
TRAIL DR4 (Trail-R)
 Ligand-induced cell death
“The death receptors”
FasL Ligand-induced trimerization

Trail
TNF

Death Domains

Death Effectors
Induced proximity
of Caspase 8
Activation of
Caspase 8
 APOPTOSIS: Signaling & Control pathways I

Externally driven Externally driven

Apoptotic signals Activators of

p53 initiator enzymes
Internally Cytochrome C
driven
Initiator caspases
mitochondrion
6, 8, 9,12
Execution caspases
2, 3, 7

Apoptosis events

Activation
 APOPTOSIS: Signaling & Control pathways II

Externally driven Externally driven

Inhibitors
Apoptotic signals Activators of
p53 initiator enzymes
Internally Cytochrome C
driven
Bcl2
External Survival
Initiator caspases Internal factors
6, 8, 9,12
Execution caspases
2, 3, 7 Inhibitors of
apoptosis
Apoptosis events

Inhibition
 The mitochondrial pathway

DNA Fas Growth factor

damage receptors
Casp8
PI3K
p53 Bid Akt
casp3
Bid BAD
Bax
Bid casp9 IAPs
Bcl2 Apaf1ATP
Bax Cyt.C casp3
Smac/
DIABLO
H2O2
AIF
Pollack etal., 2001
 REGULATION OF APOPTOSIS
Stimuli apoptosis selection of targets (Rich
et al., 2000)

Apoptosis by conflicting signals that scramble the

normal status of cell (Canlon & Raff, 1999)

Apoptotic stimulicytokines, death factors (FasL)

(Tabibzadeh et al., 1999)

DNA breaks  p53 is activated arrest cell cycle or

activate self destruction (Blaint & Vousden, 2001)
 Importance of Apoptosis
• Important in normal physiology / development
– Development: Immune systems maturation,
Morphogenesis, Neural development
– Adult: Immune privilege, DNA Damage and wound
repair.

• Excess apoptosis
– Neurodegenerative diseases

• Deficient apoptosis
– Cancer
– Autoimmunity
 FUTURE PERSPECTIVES

The biological roles of newly identified death

receptors and ligands need to be studied

Need to know whether defects in these ligands

and receptors contribute to disease
 CONCLUSION

an important process of cell death

can be initiated extrinsically through death ligands

(e.g. TRAIL, FasL) activating initiator caspase 8 through
induced proximity.

can be initiated intrinsically through DNA damage (via

cytochrome c) activating initiator caspase 9 through
oligomerization.

Initiator caspases 8 and 9 cleave and activate

effector caspase 3, which leads to cell death.
DNA DAMAGE

p53
 The bcl-2 family

N BH4 BH3 BH1 BH2 TM C

Receptor domain
Raf-1 Membrane
calcineurin Ligand
Pore anchor
domain
phosphorylation formation

Group I Bcl-2

Group II bax

Bad
Group III bid
bik
Back
 P53 & Apoptosis
p53 first arrests cell growth between G1  S

This allows for DNA repair during delay

If the damage is too extensive then p53

induces gene activation leading to
apoptosis (programmed cell death)
BACK
3 mechanisms of caspase activation
a. Proteolytic cleavage e.g.
pro-caspase 3

b. Induced proximity, e.g.

pro-caspase 8

c. Oligomerization, e.g. cyt c,

Apaf-1 & caspase 9
Back
 Apoptosis signal to kill infected cells
Cytolytic lymphocyte/CTL (& natural killer lymphocyte)
presents Fas ligand/CD178 on its surface to tell the infected
cell to die

Fas ligand

CTL Virally
infected Externally driven
Apoptotic signals
cell
Cytochrome c

Initiator caspases
The immunological
synapse holds the cells
much tighter together
Execution caspases
than shown here

Apoptosis events
Fas/ CD95 is the
‘death receptor’