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Lecture 24: "Apoptosis"

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Biology 2382B
Robert Cumming

Cell Biology Lecture No. 24: Apoptosis th Monday April 8 , 2013 Ultrastructural Features Of Apoptosis: - Apoptosis (also known as programmed cell death) is a key process that ensures normal embryonic development and proper tissue homeostasis in adult animals. Programmed cell death is an active cellular process which requires energy as opposed to necrosis (the passive form of cell death) where cells simply swell up and die. One of the key features of apoptosis is chromatin condensation as the nucleus starts to morphological changes. Apoptotic cells tend to shrink somewhat as well, and blebs (irregular bulges in plasma membrane) start to become visible. As this progresses, the blebbing continues and the nucleus actually breaks down in smaller fragments known as apoptotic bodies, which are recognized and engulfed whole by phagocytic cells in order to minimize cellular debris produced. Apoptosis also involves the cleavage of DNA by DNAases (ICAD) that cut in between nucleosomes (periodicity of about 200 base-pairs), yielding 200 base-pair fragments. Caenorhabditis elegans: -C. elegans is present as two sexes (male or hermaphrodite) and has been important for helping with discoveries about programmed cell death. As a model organism, C. elegans is incredibly advantageous due to: its small size, transparency (visible under differential interference contrast (DIC) microscopy), fully-sequenced genome, short reproductive development, and the fact that it has a defined number of cells for each sex that can be traced through a lineage (ever single cell has been mapped). Mutations In The Ced-3 Gene Block Apoptosis: -It was the mutations in the ced-3 gene that were really responsible for shedding light on the process of programmed cell death. In the early stages of C. elegans development, it was discovered that out of 1,090 newborn cells, 131 cells die during development, resulting in a nematode with exactly 959 cells. These dead cells are highly refractile and can be detected by DIC microscopy. In certain mutants of the ced-3 and ced-4 gene (ced = Cell Death Abnormal), it was observed that they contained “un-dead” cells (more than usual). They also determined that the ced-9 mutants prevented death in cells needed to survive. Role Of Capasases In Apoptotic Pathways: -Cysteine-dependent aspartate-directed proteases, or caspases, play key roles in apoptotic pathways. There are two forms of caspases present: initiator caspases (that cleave inactive pro-forms of effector caspases, thereby activating them) and effector/executioner caspases (that cleave other protein substrates within the cell, to trigger the apoptotic process). Effector caspases like ced-3 influence a variety of features associated with apoptosis: DNA fragmentation (by allowing for DNAase ICAD activation), fragmentation of nucleus (by cleaving nuclear lamins), membrane blebbing (through cytoskeletal disruption of important proteins), and fragmentation of Golgi (by influencing Golgi matrix proteins). The Apoptosome: -The Apoptosome (also known as the 1.4 megadalton “Wheel of Death”) is a large, disk-shaped heptamer of Apaf-1 (apoptotic protease activating factor 1), a protein that assembles in response to apoptosis signals and serves as an activation machine for initiator and effector caspases. Normally, Apaf- 1 exists inactive in the cytosol, but upon binding of cytochrome c (released from mitochondrial pores), Apaf-1 will form the Wheel of Death. The Apaf-1 heptamer recruits inactive caspase-9 (ced-9 initiator caspase) monomers to bind to the apoptosome in order for active caspase-9 dimers to be formed. Caspase-9 can now cleave inactive forms of downstream effector caspases (like ced-3), activating them for the process of apoptosis to be underway. The Bcl-2 Family Of Proteins: -The BcI-2 family is made of proteins that contain functional BcI homology (BH) domains (BH 1-4) and are divided into three classes: pro-survival members (have extra BH4 domain; form channels in mitochondrial outer membrane), pro-apoptotic members (missing BH4 domain) and BH3-only proteins (regulate activity of the other two classes, particularly Bcl-2 and Bax/Bak). Bcl-2 (resembles ced-9) is a pro-survival protein that inhibits apoptosis and whose high expression was found in human B-cel
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