Chapter 7 Apoptosis
General introduction PART 1
Apoptosis
Is regulated and orderly destruction of a cell through a genetically encoded
process
It is a type of “cell suicide” that is intrinsic to the cell
Active ATP dependent process
Present in many organs
25*10^6 apoptosis per second + 25*10^6 mitosis per second = 2,2 kg cells per
day
Function of apoptosis
1. Plays a major role during embryogenesis (developmental morphogenesis)–
splitting up toes and fingers – in this case also called programmed cell death
(PCD)
2. Plays a role in controlling cell numbers – every 3-5 days apoptosis renews the
epithelial layer in the intestine
3. Plays a role in removing damaged cells– damaged cells upregulate p53 and
are removed by induction of apoptosis
4. Plays a role in the negative and positive selection of lymphocytes
5. Plays a role in the induction of apoptosis in
the treatment of cancer by cytotoxic radio-
and chemotherapy (see PART 2)
Apoptosis vs Necrosis
Apoptosis Necrosis
Cell shrinkage Cell swells
Membrane blebbing (uitstulpingen) Leaky membranes (holes in the
membrane)
Organelles intact Organelles damaged
Apoptotic bodies Cell lyses
Chromatin condensation and Chromatin damaged
fragmentation
No inflammation Inflammation
Example: apoptosis in lymphocyte: lymphocyte has big nucleus and small part of
cytoplasm cell shirks membrane blebbing organelles and chromatin
condensates (nucleus becomes smaller) explosion of the nucleus apoptotic
bodies
Apoptosis signalling
, 1. Induction of apoptosis
a. Embryogenesis – programmed cell death (PCD)
b. Loss of growth factors or loss of adhesion molecule on epithelial
c. Death receptors on the TNFR family (see summary later)
d. T- and B cell antigen receptors
e. Cytotoxic T lymphocytes (CTLs)
f. DNA damage (irradiation and chemotherapy)
g. Stress conditions (increase in radicals)
2. Mitochondrial changes
3. Activation of caspase family
Caspases (cysteine-proteases) synthesizes as zymogens
They are in a normal cell as pro-caspases
They have aspartatic acid at the P1 position
14 family members are identified – 2,3,6,7,8,9 and 10 are involved in
apoptosis
Initiators: 2, 8, 9 and 10
Effectors; 3, 6 and 7
Inflammatory; 1,4 and 5
Caspase domain consist of 3 domains:
1. Pro-domain
2. Large subunit domain; contains 4 specific AA for each caspase
3. Small subunit domain
Large and small subunit domain are connected via
a spacer
Unprocessed caspase (pro-caspase) can be
cleaved and activated in 2 steps:
1. Small-subunit domain is binding to large-
subunit domain – partially processed
2. Pro-domain is removed – fully processed and
active
4. Proteolytic cleavage of structural and functional proteins
5. Induction of apoptosis morphology – removal of the cell
4 apoptosis pathways
1. Intrinsic/stress-induced or mitochondrial apoptosis pathway
2. Extrinsic/death receptor mediated apoptosis pathway
3. Granzyme B mediated apoptosis pathway
4. ER mediated apoptosis pathway
Apoptosis induced by internal signals – the intrinsic or mitochondrial
pathway
Chemotherapy, oncogene activation, DNA damage (UV-light) and cell
stress DNA p53 stabilization p53 upregulate Bcl-2 family
members (activation of BH3 only proteins) translocation of Bcl-2
family members Bak/Bax from cytoplasm to mitochondrial membrane
from homo/heterodimers result in permeabilization and
General introduction PART 1
Apoptosis
Is regulated and orderly destruction of a cell through a genetically encoded
process
It is a type of “cell suicide” that is intrinsic to the cell
Active ATP dependent process
Present in many organs
25*10^6 apoptosis per second + 25*10^6 mitosis per second = 2,2 kg cells per
day
Function of apoptosis
1. Plays a major role during embryogenesis (developmental morphogenesis)–
splitting up toes and fingers – in this case also called programmed cell death
(PCD)
2. Plays a role in controlling cell numbers – every 3-5 days apoptosis renews the
epithelial layer in the intestine
3. Plays a role in removing damaged cells– damaged cells upregulate p53 and
are removed by induction of apoptosis
4. Plays a role in the negative and positive selection of lymphocytes
5. Plays a role in the induction of apoptosis in
the treatment of cancer by cytotoxic radio-
and chemotherapy (see PART 2)
Apoptosis vs Necrosis
Apoptosis Necrosis
Cell shrinkage Cell swells
Membrane blebbing (uitstulpingen) Leaky membranes (holes in the
membrane)
Organelles intact Organelles damaged
Apoptotic bodies Cell lyses
Chromatin condensation and Chromatin damaged
fragmentation
No inflammation Inflammation
Example: apoptosis in lymphocyte: lymphocyte has big nucleus and small part of
cytoplasm cell shirks membrane blebbing organelles and chromatin
condensates (nucleus becomes smaller) explosion of the nucleus apoptotic
bodies
Apoptosis signalling
, 1. Induction of apoptosis
a. Embryogenesis – programmed cell death (PCD)
b. Loss of growth factors or loss of adhesion molecule on epithelial
c. Death receptors on the TNFR family (see summary later)
d. T- and B cell antigen receptors
e. Cytotoxic T lymphocytes (CTLs)
f. DNA damage (irradiation and chemotherapy)
g. Stress conditions (increase in radicals)
2. Mitochondrial changes
3. Activation of caspase family
Caspases (cysteine-proteases) synthesizes as zymogens
They are in a normal cell as pro-caspases
They have aspartatic acid at the P1 position
14 family members are identified – 2,3,6,7,8,9 and 10 are involved in
apoptosis
Initiators: 2, 8, 9 and 10
Effectors; 3, 6 and 7
Inflammatory; 1,4 and 5
Caspase domain consist of 3 domains:
1. Pro-domain
2. Large subunit domain; contains 4 specific AA for each caspase
3. Small subunit domain
Large and small subunit domain are connected via
a spacer
Unprocessed caspase (pro-caspase) can be
cleaved and activated in 2 steps:
1. Small-subunit domain is binding to large-
subunit domain – partially processed
2. Pro-domain is removed – fully processed and
active
4. Proteolytic cleavage of structural and functional proteins
5. Induction of apoptosis morphology – removal of the cell
4 apoptosis pathways
1. Intrinsic/stress-induced or mitochondrial apoptosis pathway
2. Extrinsic/death receptor mediated apoptosis pathway
3. Granzyme B mediated apoptosis pathway
4. ER mediated apoptosis pathway
Apoptosis induced by internal signals – the intrinsic or mitochondrial
pathway
Chemotherapy, oncogene activation, DNA damage (UV-light) and cell
stress DNA p53 stabilization p53 upregulate Bcl-2 family
members (activation of BH3 only proteins) translocation of Bcl-2
family members Bak/Bax from cytoplasm to mitochondrial membrane
from homo/heterodimers result in permeabilization and
