CHT THEO LP TRNH T

BO APOPTOSIS
T bo sinh trng, sng, cht

APOPTOSIS
Apoptosis: programmed cell death (PCD)

-L mt qu trnh cht sinh l nhm loi b c chn lc cc

t bo khng mong mun
-c im:
-T bo b nhn
- Mng t bo b phng
- Mt tip xc gia cc t bo
- DNA b ct gy bn trong cc nhim sc th
- Tng cng ngun ion Ca vo t bo
- Hot ha mt s enzym c hiu v gii phng cytochrome c khi ty
th
c im hnh thi ca t bo b apoptosis
 Con ng apoptosis

Cc tc nhn Cc phn t tham gia Hiu qu Sinh ra cc cht Cht

. FADD . Caspases . Cc protein t bo

. TRADD . DNA
. FLIP
. Bcl-2 family
. Cytochrome c
. p53
. Mdm2
 CASPASES

Caspase: cysteine-aspartic protease :

enzyme protease dng cysteine-aspartic l mt h ca protease
cysteine
C vai tr quan trng trong qu trnh cht t bo, hoi t, sng

Caspase-1 ((interleukin-1-beta converting enzyme, ICE)

Caspase-2 (ICH-1, Nedd-2)
Caspase-3 (CPP32, Apopain, Yama)
Caspase-4 (ICH-2, TX, ICEre)
Caspase-5 (ICErel, TY)
Caspase-6 (Mch2)
Caspase-7 (ICE-LAP3, Mch3, CMH-1)
Caspase-8 (FLICE, Mch5, MACH)
Caspace-9 (Mch6, ICE-LAP6)
Caspase-10 (Mch4)
Caspase-11
Caspase-12
Caspase-13
Caspase-14
C ch phn t ca cc con ng tn hiu apoptosis
 Cc con ng apoptosis chnh
Con ng th th cht Con ng ti th
FasL
Fas/Apo1 oxidants ceramide others
/CD95 DNA
damage
D D
D D D Bcl-2
FADD

DISC
Procaspase 8 dATP
Apaf -1
BID Procaspase 9
Cytochrome
Caspase 8 c
Procaspase 3
dATP
Apaf -1
Caspase 9
Cellular targets Caspase 3 apoptosome
Con ng tn hiu apopotosis thng qua th th cht
v thng qua ti th
Thng qua th th cht

Cc th th ny nm trn mng t bo:

Cc th th ny thuc th th siu h yu t hoi t u (tumor nercosis factor

receptor, TNFR) bo gm: TNFR-1, Fas/CD95 ((APO-1/CD95), v DR-4, DR-5

Cu trc TNFR:
+ Mt on bn ngoi t bo c mang nhiu cysteine ( nhn din phi t)

+Bn trong t bo c mt on gi l phn cht (death domain, DD):

Gn vi phn ny c mt phn t tip ni (adapter molecule like, FADD hoc

TRADD)
Cc phn t ny c sinh ra t phn DD ca th th cht kch thch phc h
tn hiu n t bo (death inducing signalling complex, DISC).

Trn DD, FADD c mang mt on tng hiu qu cht (death effector domain,
DED), phn ny c s tng tc qua li ca cc DED-DED v tc ng ti dng
caspase-8 ban u to ra phc h tn hiu kch thch cht t bo.
Thng qua ti th
Trong t bo, khi tn hiu truyn theo con ng th th cht khng to ra
caspase hot.

Trong trng hp ny, tn hiu cn c tng ln thng qua ng ti th.

Tn hiu lin kt gia caspase v ti th s c tr gip bi Bcl-2 (B-cell lymphoma 2)

thuc h Bid.

Bid c kch hot bi caspase 8 v chuyn vo ti th:

Ti y, kch hot dng ban u ca apoptosis thuc thnh phn Bcl-2 l Bax v Bak
kch thch sinh ra cytochrome c v cc yu t ban u apoptosis ca ti th chuyn
vo cytosol.

Cytochrome c lin kt ti Aparf-1 (ADP-ribosylation factor) lm thnh i hnh dng t

bo ph thuc vo dATP)

Sau , t bo chuyn sang dng apoptosis. Khi t bo dng apoptosis s kch hot
caspase-9.

Khi caspase-9 hot ng s ko theo caspase-3, caspase-7, capspase-6 hot ng

lm cht t bo
Ti th iu khin qu trnh apoptosis bn trong t bo
 C ch iu khin tn hiu apoptopsis
Bcl-2
Bcl-2 c 2 nhm
chnh:

+ siu h Bax
c Bax, Bak,

+Bok cc
protein ny c
cha BH1,
BH2,v BH3,

BH3 c Bid,
Bim, Bik, Bad,
Bmf, Hrk, Noxa,
Puma, Blk,
BNIP3, v Spike
iu khin tn hiu apoptosis by protein c ch apoptosis
(IAPs, inhibitors of apoptosis proteins)

-Bcl-2
- Bcl-XL
- Mcl-1
- p35 (Baculovirus)
-BHRF1 (Ebstein-Barr Virus)
- LMW5 HL (African Swine Fever Virus)
- p19 (E1B) (Adenovirus)
Mt s bnh lin quan ti mt chc nng apoptosis
Ph hy tn hiu apoptosis c th c vai tr s cp hoc th cp chng hn nh bnh:

Ung th ( tng s lng t bo, khng ti iu tr, thot khi s kim sot ca h
thng min dch)

Bnh t min, Alzheimers, Parkinson, Huntington,

PH HY QU TRNH APOPTOSIS
TRONG T BO UNG TH
Caspase c th b c ch bi virut

... CrmA
... Baculovirus p35
... Ebstein Barr Virus BHRFI protein
... Ebstein Barr Virus LMP-1 protein
Cc protein tham gia trong qu trnh apoptosis

... p53
... pRb
... Fas
... Mdm2
... c-myc
... c-Jun
... Bcl-2 family
Mt s thuc kch thch Apoptosis
Genentech BioOncology hp tc vi Amgen sn xut phi t ti t hp ca ngi
rhApo2L/TRAIL (rhApo2L/TRAIL), khng th n dng ngi l Apomab
Mc ch l : rhApo2L/TRAIL kch hot apoptosis thng qua th th th th cht
(DR4 v DR5)

+ rhApo2L/TRAIL c to ra ging nh Apo2L/TRAIL

Recombinant human Apo2L/TRAIL is engineered to mimic endogenous Apo2L/TRAIL.14
 + rhApo2L/TRAIL c thit k lin kt vi th th DR4 v DR5

+ DR4 v DR5 hot ng kch thch phc h tn hiu cht v bt u

khi ng hot ng ca caspase 8, 10 ban u
Khng th n dng ngi Apromab
Mc tiu: l phi t ca th th th DR5

Hot ng trc tip vo th th DR5

+ DR5 hot ng kch hot phc h tn hiu cht v bt u khi ng
hot ng ca caspase 8,10