Bcl-2

Bcl-2B-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…

• 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.

C. elegans Great for studying apoptosis

1090 somatic cells- 131 undergo programmed cell death

Apoptosis in C. elegans

ced-3 or ced-4 mutation

Mutation in ced-9

ced-3/ced-9 double mutant

Conclusions

• ced-3 and ced-4 required for apoptosis

• ced-9 suppresses apoptosis

• ced-3 acts downstream of ced-9

How ced proteins act together

C. elegans model

*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.

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.

Trophic Factor present

- No release of cyt C, and no caspase activity

Egl-1

ced-9

ced-4

ced-3

MITOCHONDRIAL MEMBRANE

Cytochrome C

Trophic factor absent

-release of cyt C into the cytosol

Egl-1

ced-9

ced-4

ced-3

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).

Over-expression of Bcl-2

• Leukemia

• Lymphomas

• Malignant Melanomas

• Autoimmune diseases such as rheumatoid arthritis

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.

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.