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Chết tế bào có chương trình

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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
•
•
•
•
TB sưng to
Vỡ màng
ATP bị suy yếu
TB ly giải, đáp ứng với
phản Ứng viêm
• DNA đứt gẫy ngẫu nhiên
hoặc nhòe
• Trong cơ thể, toàn bộ
vùng mô bị ảnh hưởng
Chết Tb có chương trình
•
•
•
•
TB kết đặc
Màng còn nguyên vẹn
Yêu cầu ATP
Tb bị thực bào, không có
phản ứng mô
• DNA đứt gẫy từng vạch
• Trong cơ thể, các tb đơn lẻ
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
membrane
blebbing &
changes
reduction
cell
mitochondrial
leakage
shrinkage
nuclear
fragmentation
chromatin
condensation
Hacker., 2000
APOPTOSIS: Morphological events
cell shrinkage
organelle reduction
mitochondrial leakage
chromatin condensation
nuclear fragmentation
membrane blebbing & changes
Blebbing & Apoptotic bodies
Bleb
The control retained over the cell
membrane & cytoskeleton allows intact
pieces of the cell to separate for
recognition & phagocytosis by MFs
Apoptotic body
MF
MF
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
decision
to die
131 cells
execution
ced-3
ced-4
egl-1
ced-9
ces-2
ces-1
engulfment
ced-1
ced-2
ced-5
ced-6
ced-7
ced-10
apoptosis
degradation
nuc-1
Apoptosis: Pathways
“Extrinsic Pathway”
Death
Ligands
Death
Receptors
“Intrinsic Pathway”
DNA
damage
& p53
Mitochondria/
Cytochrome C
Initiator
Caspase 8
Effector
Caspase 3
Initiator
Caspase 9
PCD
MAJOR PLAYERS IN
APOPTOSIS
•
•
•
•
Caspases
Adaptor proteins
TNF & TNFR family
Bcl-2 family
Ligand-induced cell death
Ligand
FasL
TNF
TRAIL
Receptor
Fas (CD95)
TNF-R
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
Apoptotic signals
p53
Internally Cytochrome C
driven
Externally driven
Activators of
initiator enzymes
Initiator caspases
mitochondrion
6, 8, 9,12
Execution caspases
2, 3, 7
Apoptosis events
Activation
APOPTOSIS: Signaling & Control pathways II
Externally driven
Apoptotic signals
p53
Internally Cytochrome C
Bcl2
driven
Externally driven
Inhibitors
Activators of
initiator enzymes
Initiator caspases
6, 8, 9,12
External Survival
Internal factors
Execution caspases
2, 3, 7
Apoptosis events
Inhibitors of
apoptosis
Inhibition
The mitochondrial pathway
DNA
Fas
damage
Casp8
p53
Growth factor
receptors
PI3K
Bid
Bid
Bax
Bid
Bax
Akt
casp3
BAD
Bcl2
casp9
Apaf1
ATP
Cyt.C
IAPs
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
Receptor domain
Ligand
Pore
domain
formation
phosphorylation
Raf-1
calcineurin
BH2
TM
C
Membrane
anchor
Group I
Bcl-2
Group II
bax
Group III
Bad
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
Externally driven
Apoptotic signals
Cytochrome c
Initiator caspases
The immunological
synapse holds the cells
much tighter together
than shown here
Fas/ CD95 is the
‘death receptor’
Execution caspases
Apoptosis events
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