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Bcl-2

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….

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Bcl-2

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  1. Bcl-2 B-cell lymphoma The Apoptotic Pathway

  2. What is apoptosis? Programmed cell death Regulated process leading to cell death via a series of well-defined morphological changes.

  3. 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.

  4. C. elegansGreat for studying apoptosis1090 somatic cells- 131 undergo programmed cell death

  5. Apoptosis in C. elegans ced-3 or ced-4 mutation Mutation in ced-9 ced-3/ced-9 double mutant

  6. Conclusions • ced-3 and ced-4 required for apoptosis • ced-9 suppresses apoptosis • ced-3 acts downstream of ced-9

  7. How ced proteins act togetherC. elegans model

  8. *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.

  9. 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.

  10. Trophic Factor present - No release of cyt C, and no caspase activity ced-3 Egl-1 ced-4 MITOCHONDRIAL MEMBRANE ced-9 Cytochrome C

  11. Trophic factor absent -release of cyt C into the cytosol ced-3 ced-4 Egl-1 ced-9

  12. 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).

  13. Over-expression of Bcl-2 • Leukemia • Lymphomas • Malignant Melanomas • Autoimmune diseases such as rheumatoid arthritis

  14. 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.

  15. 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.

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