bcl-2
DESCRIPTION
Bcl-2. B-cell lymphoma The Apoptotic Pathway. What is apoptosis?. Programmed cell death Regulated process leading to cell death via a series of well-defined morphological changes. The role of apoptosis…. - PowerPoint PPT PresentationTRANSCRIPT
![Page 1: Bcl-2](https://reader035.vdocument.in/reader035/viewer/2022070418/5681573e550346895dc4e4bd/html5/thumbnails/1.jpg)
Bcl-2B-cell lymphoma
The Apoptotic Pathway
![Page 2: Bcl-2](https://reader035.vdocument.in/reader035/viewer/2022070418/5681573e550346895dc4e4bd/html5/thumbnails/2.jpg)
What is apoptosis?
Programmed cell death
Regulated process leading to cell death via a series of well-defined morphological changes.
![Page 3: Bcl-2](https://reader035.vdocument.in/reader035/viewer/2022070418/5681573e550346895dc4e4bd/html5/thumbnails/3.jpg)
The role of apoptosis…
• Plays important role of population control by balancing cell proliferation and cell death.
• If cell proliferation without cell death…TUMOR!
• Also, during embryogenesis, apoptosis gets rid of unwanted cells, e.g. Development of fingers and toes, nervous system.
![Page 4: Bcl-2](https://reader035.vdocument.in/reader035/viewer/2022070418/5681573e550346895dc4e4bd/html5/thumbnails/4.jpg)
C. elegans Great for studying apoptosis
1090 somatic cells- 131 undergo programmed cell death
![Page 5: Bcl-2](https://reader035.vdocument.in/reader035/viewer/2022070418/5681573e550346895dc4e4bd/html5/thumbnails/5.jpg)
Apoptosis in C. elegans
ced-3 or ced-4 mutation
Mutation in ced-9
ced-3/ced-9 double mutant
![Page 6: Bcl-2](https://reader035.vdocument.in/reader035/viewer/2022070418/5681573e550346895dc4e4bd/html5/thumbnails/6.jpg)
Conclusions
• ced-3 and ced-4 required for apoptosis
• ced-9 suppresses apoptosis
• ced-3 acts downstream of ced-9
![Page 7: Bcl-2](https://reader035.vdocument.in/reader035/viewer/2022070418/5681573e550346895dc4e4bd/html5/thumbnails/7.jpg)
How ced proteins act together
C. elegans model
![Page 8: Bcl-2](https://reader035.vdocument.in/reader035/viewer/2022070418/5681573e550346895dc4e4bd/html5/thumbnails/8.jpg)
*Regulators: Promote or suppress apoptosis
*Adapters: Interact with regulators and effectors depending on trophic factors (extra-cellular signal).
*Effectors: Their activation leads to degradation of various intracellular substrates (caspase cascade) cell death.
![Page 9: Bcl-2](https://reader035.vdocument.in/reader035/viewer/2022070418/5681573e550346895dc4e4bd/html5/thumbnails/9.jpg)
C. elegans and Humans
• Bcl-2 was the first apoptotic gene to be cloned and isolated from human follicular lymphomas. It was shown to promote cell survival---just like ced-9.
• Bcl-2 can even block cell death when expressed in ced-9 mutant C. elegans!
• Both are localized to the outer mitochondrial membranes.
![Page 10: Bcl-2](https://reader035.vdocument.in/reader035/viewer/2022070418/5681573e550346895dc4e4bd/html5/thumbnails/10.jpg)
![Page 11: Bcl-2](https://reader035.vdocument.in/reader035/viewer/2022070418/5681573e550346895dc4e4bd/html5/thumbnails/11.jpg)
Trophic Factor present
- No release of cyt C, and no caspase activity
Egl-1
ced-9
ced-4
ced-3
MITOCHONDRIAL MEMBRANE
Cytochrome C
![Page 12: Bcl-2](https://reader035.vdocument.in/reader035/viewer/2022070418/5681573e550346895dc4e4bd/html5/thumbnails/12.jpg)
Trophic factor absent
-release of cyt C into the cytosol
Egl-1
ced-9
ced-4
ced-3
![Page 13: Bcl-2](https://reader035.vdocument.in/reader035/viewer/2022070418/5681573e550346895dc4e4bd/html5/thumbnails/13.jpg)
Bcl-2 and Cancer
• What exactly leads to the over-expression of
Bcl-2?t (14,18) chromosomal translocation
it is a transcriptional unit at this breakpoint and has deregulated high level of expression due to juxtaposition to enhancer elements. (found in ~85% of human follicular lymphoma cases).
![Page 14: Bcl-2](https://reader035.vdocument.in/reader035/viewer/2022070418/5681573e550346895dc4e4bd/html5/thumbnails/14.jpg)
Over-expression of Bcl-2
• Leukemia
• Lymphomas
• Malignant Melanomas
• Autoimmune diseases such as rheumatoid arthritis
![Page 15: Bcl-2](https://reader035.vdocument.in/reader035/viewer/2022070418/5681573e550346895dc4e4bd/html5/thumbnails/15.jpg)
Malignant Melanoma
• Bcl-2 expression found in up to 100% of cases and high Bcl-2 expression associated with shorter survival.
• Chemoresistance has been linked to expression of BCL2. Why? Think about how traditional treatments work.
![Page 16: Bcl-2](https://reader035.vdocument.in/reader035/viewer/2022070418/5681573e550346895dc4e4bd/html5/thumbnails/16.jpg)
Treatments Targetting Bcl-2
• Antisense oligonucleotides– Chemically synthesized, highly purified sequences of single-
stranded DNA that are complementary to specific coding regions of mRNA, inhibiting gene expression.
– Augmerosen is complementary to the first 6 codons of Bcl-2 mRNA and hybridizes to the target RNA bases decrease in concentrations of RNA and protein product.
– More studies needed, but Augmerosen and similar treatments, combined with traditional chemotherapy could be effective in combating malignancy.