Lecture 39 – Caspases and Cancer December 2, 2013
(Definition): Caspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed
proteases are a family of cysteine proteases that play essential roles in apoptosis (programmed cell
death), necrosis, and inflammation. Caspases are essential in cells for apoptosis, or programmed cell
death, in development and most other stages of adult life, and have been termed "executioner" proteins
for their roles in the cell. Some caspases are also required in the immune system for the maturation of
lymphocytes. Failure of apoptosis is one of the main contributions to tumor development and
autoimmune diseases; this, coupled with the unwanted apoptosis that occurs with ischemia or
Alzheimer's disease, has stimulated interest in caspases as potential therapeutic targets since they were
discovered in the mid-1990s.
• Cysteine Endopeptidases – meaning that they are enzymes that cleave peptides at a cysteine
followed by an aspartic acid residue.
• These caspases become active after a proteolytic cleavage on their inactive precursor yields
large and small subunits that form the enzyme.
• One caspase can be the proteinase of the next caspase, eventually a final caspase cleaves DNA
• Because there are a number of caspases in the pathway, there is amplification, so DNAat the
end of the pathway can be cleaved at a large scale.
Apoptosis in Development
• Retinal ganglion cells project into the brain, but if they do not form active synapses, i.e. they
don't go into the right area of the brain, the neurons die. Thus there are many more embryonic
neurons than in the mature creature.
• Adrenal Tumors often disappear by themselves because they are composed of neural tissue and
die off when they don't form the correct synapses. Sometimes however, the tumor doesn't
• Extrinsic Pathway - In cells there are death domains (e.g. tumor necrosis factor), which are
receptors that activate caspase synthesis.
• Intrinsic Pathway – Members of the Bcl2 family (originally discovered in B-cell leukemia)
either inhibit or trigger Apoptosis.
◦ Bcl2 proteins, when activated, create pores in the outer mitochondrial membrane.
◦ This causes the release of cytochr