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Programmed Cell Death

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Laura Parker

Programmed Cell Death Cell death  critical to embryonic development, tissue homeostasis, establishment of immune self-tolerance, and for regulation of cell viability by hormones and growth factors Apoptosis  programmed cell death characterized by distinct morphological changes in the dying cell • Shrink • Membrane blebs form at plasma membrane • Intracellular organelles disassemble • Chromatin condensed and cleaved • Finally, packaged into membrane bound apoptotic bodies Apoptosis  neat form of cell death (necrosis usually initiates inflammatory response) 2 phases of apoptosis: • Cells are committed to undergo apoptosis during the latent phase o Extremely variable in length o Cells may look normal o Once past point of no return, no rescue possible • Execution phase o Undergo dramatic morphological changes o Extremely rapid compared to latent phase Apoptosis is mediated by an intracellular proteolytic cascade • Caspases o Cystein proteases that cleave at specific aspartic acid residues o Responsible for dissembling the apoptotic cell o Synthesized as procaspases (inactive precursors), and are activated by cleavage o Active caspase is heterotetramer of 2 large and 2 small subunits o Classifications  Initiator caspases  can be autoactivated when complexed with appropriate scaffolding (have long prodomains that interact with other proteins)  Effector caspases  activated by cleavage by initiator caspases Activation of initiator complexes  2 general pathways • Extrinsic  signal comes from outside of the cell o Example – ligation of a death receptor on the plasma membrane • Intrinsic  signal comes from within the cell o DNA damage that cannot be prepared o Usually involves mitochondria Adaptor proteins  have multiple protein-protein interaction motifs and assemble after pro-apoptotic stimuli to activate these initiator caspases • Example – ligand outside the cell binds to a death receptor, such as Fas or TNFα o Caspase 8 is ciritcal initiator caspase in this pathway • Another well studied pathway is activated by the release of critical mitochondrial factors from the intermembrane space, including cytochrome C o Cytochrome c and dATP associate with the adaptor protein Apaf-1, which then recruits procaspase-9 and induces autoactivation Proteolytic cascade • Once an initiator caspase activated, it can cleave and activate downstream effector caspases (i.e. casp 3) o This sets off an irreversible proteolytic cascade o Effector casp cleave a variety of cellular structural proteins and regulatory proteins o Diff casp recognize dif
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