How cell death occurs by Hussein Sabit

1. Carcinogenesis and
Apoptosis
Hussein Sabit, PhD
College of Biotechnology, Misr University for science and Technology

2. What is cancer?
Cancer is uncontrolled cell proliferation.
It arises from:
1. Irreversible genetic damage to cell’s
DNA.
2. Block in normal process of
differentiation.
3. Block in apoptosis.

3. Phenotype of a cancer cell
Six Hallmarks of Cancer cell:
1. Self-sufficient growth signals
Constitutively activated growth factor
signalling.
2. Resistance to anti-growth signals
Inactivated cell cycle checkpoint.
3. Immortality
Inactivated apoptosis pathway.

4. Cont.
4. Resistance to cell death
Activated anti- cell death signalling.
5. Sustained angiogenesis
Rapid formation of blood vessels.
Activated VEGF signalling.
6. Invasion and metastasis
Loss of cell-to-cell interactions.

5. Proto-oncogenes
• Normal growth factor genes that become
oncogenes (cancer-causing) when
mutated.
• Stimulates cell growth.
• If switched “ON” can cause cancer.

6. Tumor Suppressor Genes
 Regulates the cell cycle and, thus,
functions as a tumor suppressor that
is involved in preventing cancer.
 In humans, p53 is encoded by the
TP53 gene located on the short arm
of chromosome 17 (17p13.1).

7. P53 Tumor Suppressor Gene
• The most frequently mutated gene in
human cancers.
• Critical roles:
– Prevents mutations and repairs DNA
– Cell cycle arrest in G1
• Also responsible for the activation of
several proteins involved in
apoptosis.
– Mutant p53 has lost ability to activate
apoptosis.

8. p53 Tumor Suppressor Gene
• Mutated (switched OFF) in more than
50% of all cancers.
• p53 regulates (activates or represses)
transcription of more than 50 different
genes.
• Activated p53 levels rise rapidly if DNA
is damaged to repair, or if the damage
is severe ..leading to apoptosis.

9. Cancer is easy to happen !!
• In order for an oncogene to cause cancer,
only one copy must be mutated.
• A tumor suppressor gene must be
completely absent to allow cancerous
cell division to occur.

10. The cell will
normally functions
as the two pulling
forces are equal.

11.  Cell will
continue to grow
as one copy of
proto-oncogene
is mutated.
 Its pulling force
is overriding
that of TSG.

12.  Both copies of
TSG are
deactivated
while the proto-
oncogene is
normal.
 The growth is
not controlled..
Leading to
cancer.

13. Now!
Apoptosis should be in
balance with Mitosis

14. Because apoptosis is the default
disposal system to delete abnormal
cells,
It is .. Our subject

15. Apoptosis:
The secret of life
“Life cannot exist without
cellular death”

16. Road map
 What is apoptosis?
 Different types of cell death.
 Caspases, the main executioner of apoptosis.
 Types of apoptosis.
 Lack & excess of apoptosis.

17. Is Apoptosis so complicated like this?
Actually .. YES !!

18. From the beginning ..
The word Apoptosis is from Greek:
Apo means off/without, ptosis means
falling.
Apoptosis means falling off.

19. Cells may:
Die for the sake of life !!

20.  cells die each day in
average adult human due to apoptosis.
 For a child aged 8-14, about 25 billion
cells die each day.
60 billion

21. What is Apoptosis?

22. Apoptosis .. is a normal, genetically
regulated process leading to the death of
cells and triggered by the presence or
absence of certain stimuli, as DNA
damage.

23. Cont.
 Apoptosis (PCD) is an orchestrated collapse of
a cell, protein degradation, DNA
fragmentation followed by rapid engulfment
of corpses by neighboring cells.
 Essential part of life for every multicellular
organism from worms to humans.
 Apoptosis plays a major role from embryonic
development to senescence.

24. Apoptosis .. Where it
happens?

25.  Phylogenic: the loss of tail during the
development of tadpole.

26.  Morphogenic: the loss of mesenchyme
between the digits.

27. • Histogenic: the reduction of numbers of
neurons in the developing brain.

28. Too much:
 Alzheimers’
 Parkinson’s
 Huntington’s
 AIDS
 Stroke
Too little:
 Cancer
 Autoimmunity
 Persistent
infections
Apoptosis is a balanced act

29. Many types of cell death
 Necrosis is a non-apoptotic accidental cell
death. Morphological changes are seen
only after a cell has already died.
 Autophagy is the degradation of cellular
components within dying cells in an
autophagic vacuole.

30. Cont.
 Oncosis is a prelethal pathway leading to cell
death; accompained by cellular swelling,
organelle swelling, and increased membrane
permeability.
 Pyroptosis is induced by infection with
Salmonella and Shigella.

31. Apoptosis vs. Necrosis
• A pathological response
to injury.
• Chromatin clumping.
• Mitochondria swelling
and rupture.
• Plasma membrane lyses.
• Cell contents spill out.
• A normal response to
suicide signals.
• Chromatin condenses.
• Internucleosomal cleavage
of DNA.
• Cytoplasma shrinks without
membrane rupture.
• Blebbing of plasma
membrane
Necrosis Apoptosis

32. Apoptosis Necrosis
Apoptosis vs. Necrosis

33. Apoptosis pathways
o Two alternative pathways that initiate
apoptosis:
 Extrinsic pathway
 Intrinsic pathway
o In both pathways, caspases are activated to
cleave cellular substrates, and this leads to
the biochemical and morphological changes
that characterize apoptosis.

34. So ..
The main executioner of
apoptosis are
Caspases

35. Caspases ..
Are a family of cysteine-rich proteases
that play essential roles in apoptosis.
It cuts only at aspartic acid residue.

36. Two types of Caspases ..
 Initiator caspases .. trigger the onset of
apoptosis by activating the caspases cascade.
• e.g., CASP2, 8, 9, and 10.
 Executioner caspases .. undertake the
actual work of destroying critical components of
the cell.
• e.g., CASP3, 6, and 7.

37. Other caspases
 CASP1, 4 and 5, are not currently involved in
apoptosis and rather they are involved in T-
cell maturation.
 CASP14 is not involved in apoptosis or
inflammation, but instead is involved in skin
cell development.

38. What
activates the caspase cascade
and then apoptosis?

39. Caspase activation

40. Cascade of activation

41. Again . .
The two pathways of apoptosis are:
Extrinsic pathway
Intrinsic pathway

42. Extrinsic pathway
 Initiated by extracellular signal molecules
belonging to the TNF family (eg., TNFα and
TRAIL).
 These molecules recognize and activate their
corresponding receptor on the cell
membrane.
 DISC (death-inducing signalling complex) is
then activated.

43.  DISC recruits and promotes the
activation of the initiator procaspase 8.
 Caspase 8 will then activate caspase 3
that mediated cell killing.

44. Extrinsic pathway

45. This pathway is mediated by:
 Cytochrome C
 Bcl-2 family members
 APAF-1 (apoptotic protease-activating factor 1)
Cytochrome C is released from the mitochondrion
and associates with APAF-1 constituting the
apoptosome. This structure binds to procaspase-9
promoting its activation, and then activating caspase
3 to start degradation of proteins.
Intrinsic pathway

46. Intrinsic pathway
The wheel of death

47. Apoptosome: “the wheel of death”

48. Video
https://www.youtube.com/watch?v=DR80Huxp4
y8&list=PLD0444BD542B4D7D9&index=4

49. Cell ..
Is it critical to die?

50.  Apoptosis is used for many purposes. During the
development of embryos, organs are shaped by
building oversized structures and then removing
the cells that aren't needed.
 For instance, during development of the
nervous system, half of the neurons die, leaving
the proper neural wiring. If you have watched a
tadpole lose its tail, you have also seen
apoptosis in action.

51. Why is apoptosis so
important?

52. Apoptosis and diseases
 Too much apoptosis leads to
neurodegenerative diseases, such as
Parkinson’s diseases, Alzheimer’s diseases.
 Too little apoptosis leads to cancers,
autoimmune diseases (e.g., diabetes type I).
 Some cardiovascular diseases and liver
diseases are also related to apoptosis.

53.  Philosophers have spent many centuries
searching for the meaning of life.
 In recent decades cell biologists have
become even more fascinated by the
meaning of death.
Finally ..

54. Thank you !!