The document discusses apoptosis, a regulated form of cell death crucial for development and cellular homeostasis, outlining its historical context, pathways, and roles in various diseases. It highlights both the beneficial and detrimental effects of apoptosis, such as its involvement in cancer and neurodegenerative diseases. Future research directions include studying new death receptors, understanding apoptosis mechanisms, and potential applications in treatment and prognosis.

1. APOPTOSIS
Imran Ahmad
Immunotoxicology Division
CSIR-IITR

2. Contents
 Introduction
 Importance of apoptosis
 Historical perspective
 Phenotype and Biochemical Markers
 Pathways of Apoptosis
 Apoptotic role in disease
 CSIR-IITR Contribution
 Summary and Future Perspectives

3. Introduction
Apoptosis can be defined as a pathway of cell death that
induced by tightly regulated intracellular program in which
cells destined to die, activating certain enzymes hat
degrade cell’s own DNA, and nuclear and cytoplasmic
proteins.

4. Importance of Apoptosis
Apoptosis is a necessary evil, part of normal developmental
process, specifically helps in proper development of organs,
pattern formation and digitation.
Source: Google Images

5. Apoptosis is part of normal cell development for immunocytes

6. Apoptosis: Historical perspective
1842 Carl Vogt: Principle of apoptosis
1885 Walther Flemming: Process of programmed cell death
1965 John Foxton Ross Kerr : distinguish apoptosis from
traumatic cell death by electron microscopy
2002 Nobel Prize in medicine
NATURE REWIEWS I Molecular Cell Biology Macmillan Magazines Ltd, Vol-2 2006

7. Phenotype of Cellular Apoptosis
 Membrane blebbing but no loss of integrity
 Aggregation of chromatin at the nuclear membrane.
 Begins with shrinkage of cytoplasm and condensation
of nucleus.
 Ends with fragmentation of cell into apoptotic bodies
Source: http://www.utm.utoronto.ca/

8. Biochemical markers of Apoptosis
1) A number of activities take place
 Occupation of death receptors
 Dimerization of Bcl-2 family members
 Release of cytochrome c
 Activation of caspases
 Activation of DNAse
2) Translocation of phosphatidylserine
3) ATP-dependency
4) Internucleosomal DNA fragmentation (ladder pattern)
5) No inflammation

9. A. Receptor pathway (Extrinsic pathways, physiological):

10. B. Intrinsic (mitochondria mediated) pathway:

11. Central Regulator of Apoptosis:
(1) B-cell lymphoma 2 (Bcl-2) family proteins
•Pro-survival (or anti-apoptotic) proteins having all four BH domains .
They are oncogenic when overexpressed and regulate mitochondrial
apoptotic signaling. However, Bcl-XS, a splice variant of Bcl-XL has BH4
but lacks BH1 and BH2.
•Pro-apoptotic- Bax and Bak lack the BH4 domain, and are. Ectopic or
overexpression of Bax, induces mitochondrial cytochrome c release.
•Strongly pro-apoptotic have only BH3-domain. The non-homologous
regions of BH3-only proteins could provide links to apoptotic signaling
systems.

12. D Westphal, Cell Death and Differentiation (2014) 21, 196–205
Regulation of Bcl-2 Family Proteins

13. Large domain
Small
Small
Large domain
Active caspase
Pro-domain Large domain Small
Pro-caspase
 cysteine-dependent aspartate-directed proteases
 Agents of demolition
(2) Caspases
 Caspases recognize four amino acid N-terminal to the
cleavage site-aspartic acid with high substrate specificity.
Cell Death and Differentiation (2014) 21, 196–205

14. Apoptosis
Too Much
Neurodegeneration
Thin Skin
Too little
Cancer
Artherosclerosis

15. Apoptosis
Cancer AIDS
Preclampsia of Pregnancy
Autoimmune
diseases
Ankylosing
Spondylitis,, Multiple
sclerosis,
Rheumatoid Arthritis,
Autoimmune
Lymphoproliferative
Syndrome (ALPS)
Nuorodegenerative
Diseases
Alzheimer’s Disease ,
Parkinson’s Disease,
Huntington’s Disease,
Amyotrophic Lateral
Sclerosis
Apoptosis: Role in Diseases

16. Apoptosis: Role in Cancer
Rebecca SY Wong , Journal of Experimental & Clinical Cancer Research,2011

17. Kapoor R, Kakkar P (2012) PLoS ONE 7(8): e41663. doi:10.1371/journal.pone.0041663
http://journals.plos.org/plosone/article?i d=info:doi/10.1371/journal.pone.0041663
Protective Role of Morin, a Flavonoid, against High Glucose
Induced Oxidative Stress Mediated Apoptosis in
Primary Rat Hepatocytes

18. Translocation of apoptotic mitochondrial
resident proteins

19. Summary
 Programmed cell death which occurs in multicellular organisms.
 Characterized by specific morphological and biochemical features.
 Triggered by multi-signal pathways and regulated by extrinsic and
intrinsic ligands.
 Disordered apoptosis may lead to carcinogenesis and participates in
the pathogenesis of Alzheimer disease, Parkinson disease, AIDS etc.

20. Future perspectives
 The biological roles of newly identified death receptors and ligands need to be
studied.
 Need to know whether defects in these ligands and receptors contribute to
disease.
 Understanding the mechanisms of apoptosis, and other variants of programmed
cell death.
 Understanding the mechanisms involved in physiological as well as in disturbed
or dysregulated apoptosis may lead to the development of new methods of
preventive treatment of various developmental abnormalities.
 Detection of apoptosis-related proteins may be of importance in the prediction of
patients response to chemo or radio therapy as well as of survival rates.

21. …..THANK YOU
“Life is pleasant, Death is Peaceful,
It’s the transition that’s troublesome”
-Isaac Asimov