Molecular BIology of Cancer Topics             

Bcl-2

Apoptosis

Cells respond to combinations of diverse external and internal signals. Sometimes these signals point the cells to "comit suicide", ie. to undergo apoptosis.

Apoptosis is different from cell death by necrosis. Necrosis is cell death by ‘poisoning’; it is slow,
aAffects many cells at once, and is associated to an inflammatory response.

Apoptosis is more a programmed cell death, cell ‘suicide’. It occurs rapidly (< 30 minutes), affecting only one cell amid many healthy cells. There is no inflammatory response asociated with apoptosis because the apoptotic cell bodies are destroyed (?). Every cell has the capacity to commit apoptosis as part of normal physiological processes like development (e.g. digit formation), tissue remodeling in wound repair and mammary gland involution after lactation.

Apoptosis is an organized process that follows certain steps:

  1. Nuclear and cytoplasmic condensation, separation from neighboring cells
  2. DNA fragmentation into nucleosomal fragments
  3. Sloughing off of apoptotic cell bodies
  4. Engulfment of apoptotic cell bodies by a healthy neighboring cell
  5. Engulfment of apoptotic cell bodies by macrophages

There is a delicate balance to achieve homeostatic levels of cell growth and cell death. Cancer can arise from an increase in cell proliferation and/or a decrease in cell death.

Several diseases result from disregulation of cell death. Diseases resulting from the inhibition of apoptosis include cancer, autoimmune diseases like lupus, and viral infections. Diseases resulting from increased apoptosis include AIDS, neurodegenerative disorders (Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis), ischemic injury (myocardial infarction, stroke) and toxin-induced liver disease (e.g. from alcohol).

Bcl-2

Bcl-2 protects cells from death. Both anti-apoptotic and pro-apoptotic Bcl-2 related proteins insert an alpha helix into the mitochondrial outer membrane. Proapoptotic proteins such as Bax disrupt the mitochondrial outer membrane potential, making the membrane leaky. Mitochondrial proteins such as cytochrome c then escape the mitochondrion into the cytoplasm. Antiapoptotic proteins such as Bcl-2 intertwine their alpha helix with that of a proapoptotic protein and block its membrane-disrupting effect.

Once outside the mitochondria, cytochrome c associates with Apaf-1, dATP and pro-caspase 9, thus activating the caspase 9. Caspase 9 is then able to activate other the effector caspases (e.g. caspase 3), which in turn "chop up" cellular proteins and activate other molecules responsible for destroying lipids and nucleotides Caspase 3 cleaves and inactivates ICAD (inhibitor of CAD), leaving CAD (caspase activated deoxyribonuclease) free and active. Once released cad enters the nucleus and degrades chromosomal DNA.

Experimental Results:

The bcl-2 oncogene was overexpressed in human follicular B-cell lymphomas (FDC-P1 cells) which need IL-3 (F) to survive (compare panel b to panel a).

FDC-P1 cells were transfected with bcl-2 and/or myc oncogenes and analyzed after 3 days in the presence or absence of IL-3 (F). Bcl-2 had no effect on cell proliferation (panel c is similar to panel a) but it increases the number of cell suviving after removal of IL-3 (panels d and f). Myc had no effect (panels e and f)

 

Bcl-xl

Activation of Akt/PKB by PI3K membrane lipid products leads to the phosphorylation of the proapoptotic factor Bad on a serine residue, resulting in its dissociation from Bcl-xl. Released Bcl-xl is then capable of suppressing apoptosis. Transgenic mice that overexpress Bcl-xl have lower rates of apoptosis.

Down-modulation of he apoptotic pathways contributes to tumor progression from angiogenic precursors. For example, some tumors have an increased expression of anti-apoptotic factors like Bcl-xl at angiogenesis. Apoptosis decreases with tumor progression. Bcl-xl overexpression increases tumor incidence and multiplicity.

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