Lecture: chapter 7 apoptosis
Definition of apoptosis:
= the regulated and orderly destruction of a cell through a genetically encoded process also known as
programmed cell death PCD
= type of cell suicide that is intrinsic to the cell
• Organized, neat and tidy -> leaving behind little evidence of the preexisting cell
• The cell undergoing apoptosis is swept clean during phagocytosis by macrophages,
neighboring cells that recognize molecular flags (phosphatidyl serine)
• Cell shrinkage, membrane blebbing and budding, and chromatin condensation and precise
fragmentation -> neat disposal of the cell
Contrast to necrosis: cells swell, cell membranes become leaky, and cells spill out their contents into
the surrounding tissue and cause inflammation.
• Caspases: catalyze proteolysis -> break down cellular components
25 x 10^6 mitosis per second
25 x 10^6 apoptosis per second
2,2 kg cells per day!
Function of apoptosis:
= Active ATP dependent process
• Developmental morphogenesis
• Controls cell numbers (intestines)
• Removal of damaged cells
• Negative and positive selection of lymphocytes in lymphoid organs (ig spleen)
• Cytotoxic effect of radio-and chemotherapy
,Apoptosis vs necrosis:
Necrosis: external factor induces the process, in heart attacks is necrosis
Differs in morphology! No inflammation vs inflammation!!
A= normal lymphocyte. Small cyptoplasm surrounding the nucleus
B= cell lymhpcote is ….
C= cyoses
D= chromatin is..
E= apoptotic burns
BOEK UITLEG
Leukemia gets drugs MGG or Dapi (fluorescent)
Condensated chromatin is dark purple tov light purple in apoptotic cells
, 7.1 Molecular mechanisms of apoptosis
Apoptosis signalling:
➔ Induction of apoptosis:
- Programmed
- Loss of growth factors, of adhesion
- Death receptors of the TNFR family
- t- and b- cell antigen receptors
- CTLs (cytotoxic t lymphocytes)
- DNA damage (irradiation, chemotherapy)
- Stress conditions
➔ Mitochondrial changes
➔ Activation of the caspase family
➔ Proteolytic cleavage of structural and functional proteins
➔ Induction of apoptosis morphology
Extracellular signals = death factors.
Internal signals= DNA damage, oxidative stress
Caspases:
= specific proteases that act like molecular scissors to cleave intracellular proteins at aspartate
residues.
• Cysteine-rich aspartate proteases, synthesized as zymogens (procaspases)
• Requirement for an aspartic acid at the P1 position
• 14 family members cloned
• Caspases 2,3,6,7,8,9 and 10 are involved in apoptosis
Initiators: 2,8,9,10 = up-stream -> activate downstream 3,6,7
Effectors: 3,6,7
Inflammatory: 1,4,5
9= intrinsic
8= extrinsic
, Cleavage results in activating. But first the pro-domain needs to be removed
QACxG
4 apoptosis pathways:
ER = neurodegenerative diseases (cascades 1,4,5)
Granzyme b= less research
1 and 2 have the most focus!
