apoptosis physiology programm cell death

1. Necrosis
Intrinsic Pathway
Extrinsic pathway
Caspases
Web-
footed
chicken
Bax
Cyt c
Bid
BMPs
Apoptosis
Programmed Cell
Death

2. Contents 1
2
3
Part 01 / APOPTOSIS
Part 02 /MECHANISM AND
PATHWAY
Part 03 /IMPORTANCE

3. 1
Part 1
APOPTOSIS

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INTRODUCTIO
N
• Apoptosis is a process of programmed cell death
• The demise of cells by programmed cell death is marked by a well-
defined sequence of morphological changes, collectively referred to as
apoptosis, a Greek word that means "dropping off" or "falling off" like
leaves from a tree.
• Biochemical events lead to characteristic cell changes (morphology) and
death. These changes include blebbing, cell shrinkage, nuclear
fragmentation, chromatin condensation and chromosomal DNA
fragmentation.
• Between 50 and 70 billion cells die each day due to apoptosis in average
human adult. In childrens approx. 20 to 30 billion cells die a day.

5. HISTORY
• German Scientist Carl Vogt was first to describe the principle of
apoptosis in 1842.
• In 1972 Kerr first introduced the term apoptosis in publi ation.
• Kerr received the Paul Ehrich and Ludwig Darmstaedter Prize on
March 14, 2000 for his description of apoptosis.
• The 2002 Nobel Prize in medicine was awarded to Sydney
Brenner, Horvitz, John E. Sulston for their work identifying
genes that control apoptosis.

6. Cell Death and its Regulation
• Regulated cell death is a counterintuitive, but essential,
process in metazoan animals.
• During embryogenesis, the programmed death of specific
cells keeps chicken feet as well as our hands from being
webbed.
• It also prevents our embryonic tails from persisting and our
brains from being filled with useless nerve connections.
• Many kinds of muscle, epithelial, and white blood cells
constantly wear out and need to be removed and replaced.

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• Cell-cell interactions regulate cell death in two fundamentally
different ways.
• First, if not all, cells in multicellular organisms require specific
protein hormone signals to stay alive.
• In the absence of such survival signals, frequently referred to as
trophic factors, cells activate a "suicide" program.
• Second, in some developmental contexts, including the immune
system, other specific hormone signals induce a murder"
program that kills cells.
• Whether cells commit suicide for lack of survival signals or are
murdered by killing signals from other cells, cell death is most
often mediated by a common molecular pathway, termed
apoptosis.

8. NECROSIS
• A different form of cell death, necrosis, occurs when cells are
subjected to injury or excessive stresses such as heat, absence of
oxygen, or infection by pathogens.
• Necrosis creates holes in the plasma membrane, causing
leakage of intracellular contents.
• Perhaps surprisingly, one form of necrosis, termed necroptosis,
is often triggered by extracellular hormones such as tumor
necrosis factor alpha (TNF alpha).
• Activation of this cell-death pathway frequently causes
inflammation and contributes to the development of many
human diseases, including nerve degeneration and athero
sclerosis.

10. Web-footed Chicken
• During the development of many vertebrate limbs, cells in the
soft tissue between the embryonic digits undergo programmed
cell death. In the chi ken foot, this process leads to the
formation of four separate toes.
• During chicken foot development, bone morphogenetic
proteins (BMPs) are expressed by interdigital cells and induce
apoptosis.
• A dominant-negative type I BMP receptor was expressed in a
developing chicken foot, blocking BMP signalling and
preventing the programmed cell death that normally occurs.
• This manipulation allowed the survival of cells that then
divided and differentiated into web.

11. • The similarity of this webbing to webbed duck feet led to
studies showing that BMPs are not expressed in duck
interdigital cells.
• These results indicate that BMP signalling actively mediates
cell death in the embryonic limb.

12. MORPHOLOGIC HALLMARKS OF
APOPTOSIS
• Dying cells shrink, condense, and then fragment, releasing small
membrane-bound apoptotic bodies.
• Within these apoptotic cells, nuclei condense, and the DNA is
condensed.
• Early in apoptosis, dense chromosome condensation occurs along the
nuclear periphery.
• The cell body also shrinks, although most organelles remain intact.
• Later, both the nucleus and the cytoplasm fragment, forming apoptic
bodies, which are phagocytised by surrounding cells.
• The apoptotic bodies are engulfed by macrophages and thus are
removed from the tissue without causing and inflammatory response.

14. 2
Part 2
MECHANIS
M AND
PATHWAY

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CASPASES: THE EXECUTORS
• Caspases or cysteine-aspartic proteases are a family of cysteine
proteases that play essential roles in apoptosis (Programmed Cell
Death), necrosis and inflammation.
• Single chain of pro-enzymes.
• Contains an N-TERMINAL domain, a small subunit, and a large
subunit (similar to ribosomes).
• Apoptotic stimulus, Activation, Substrate cleavage, Enzyme.
• All caspases are synthesized as inactive form and is converted in to
active form by proteolytic clevage catalysed by other caspases.
• The activated caspases mediate the events of apoptosis.

16. 3 types of Caspases
• Inflammatory Caspases: 1, 4 and 5
• Initiator Caspases: 2, 8, 9 and 10
1. Long N-terminal domain
2. Interact with effector caspases
• Effector Caspases: 3, 6 and 7
1. Little to no N-terminal domain
2. Initiate cell death

17. ACTIVATION MECHANISMS
• The initiation of apoptosis is tightly regulated by activation
mechanisms, because once apoptosis has begun, it inevitably leads
to the death of the cell.
• The two best-understood activation mechanisms are the intrinsic
pathway (also called the mitochondrial pathway) and the extrinsic
pathway.
• The intrinsic pathway is activated by intracellular signals generated
when cells are stressed and depends on the release of proteins from
the intermembrane space of mitochondria.
• The extrinsic pathway is activated by extracellular ligands binding to
cell-surface death receptors, which leads to the formation of the
death-inducing signaling complex (DISC).

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• In mammalian cell a major pathway leading to cell cycle
arrest in response to DNA damage is mediated by
transcription factor p53.
• Activation of tumor suppressor protein p53 lead toDNA
damage and also lead to apoptosis; this is from
transcriptional activation of genes encoding the BH-3 only
proapoptotic BCl-2 family.
• Increased expression of BH-3 leads to the acivation of Bax
&Bak (Pro-apoptotic proteins) release of cytochrome from
mitochondria, activation of caspase-9

19. INTRINSIC PATHWAY
• The intrinsic signalling pathway for programmed cell death involves
non-receptor -mediated intracellular signals, including activities in
the mitochondria that intiate apoptosis.
• Stimuli for the intrinsic pathway include viral infections and damage
to the cell toxins, free radicals, or radiation.
• Damage to the cellular DNA can also induce the activtion of the
intrinsic pathway for programmed cell death.
• Pro-apoptotic proteins activate caspases that mediate the
destruction of the cell through many pathways. These proteins also
translocate into the cellular nucleus, inducing apoptosis, inducing
DNA fragmentation, a hallmark of apoptosis.

20. • The regulation of pro-apoptotic events in the mitochondria
occurs through activity of the members of the Bcl-2 family
of proteins and the tumour suppressor protein p53.
• Members of the Bcl-2 family of proteins may be pro- or
anti-apoptotic.
• The anti-apoptotic proteins are Bcl-2, Bcl-x, Bcl-Xl, Bcl-Xs,
Bcl-w and BAG.
• Pro-apoptotic proteins include Bcl-10, Bax, Bad, Bak, Bid,
Bim, Bik and Blk.

22. EXTRINSIC PATHWAY
• The extrinsic signalling pathway leading to apoptosis involves
transmembrane death receptors that are members of the Tumour
Necrosis Factor (TNF) receptor gene superfamily. Members of this
receptor family binds to extrinsic ligands and transduce intracellular
signals that ultimately result in the destruction of the cell.
• The most well characterised ligands of these receptors to date are
FasL, TNF-alpha, Apo3L and Apo2L. Corresponding receptors are
FasR, TNFR1, DR3, and DR4/DR5, respectively.
• The signal transduction of the extrinsic pathway involves several
caspases which are proteases with specific cellular targets. Once
activated, the caspases affect several cellular functions as part of a
process that results in the death of cells.

24. 3
IMPORTANC
E
Part 3

25. 1. Important in normal physiology / development
• Development: Immune systems maturation,
Morphogenesis, Neural development.
• Adult: Immune privilege, DNA da.age and Wound
repair.
1. Excess apoptosis
• Neurodegenerative disease
1. Deficient Apoptosis
• Cancer
• Autoimmunity

26. THANK YOU