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Caspases and Cancer.docx

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BIOL 3096
Joel Sheffield

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. Caspases • 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 sequences. • 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 dissipate. • 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
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