Overview Programmed cell death requirements ATP functioning caspase enzymes for cellular degradation break down cytoskeleton degrade DNA endonucleases cut at internucleosomal regions, resulting in segments that are multiples of 180 base pairs Two pathways intrinsic occurs in response to cell injury, loss of stimulatory growth factors, or DNA damage involved in embryogenesis mediated by changes in levels of anti-apoptotic (Bcl-2) and pro-apoptotic (Bax) factors leads to ↑ mitochondrial permeability and release of cytochrome c release of cytochrome c activates caspase-9 Bcl-2 binds to cytochrome c preventing apoptosis and inhibits Apaf-1 (promotes activation of caspases) overexpression of Bcl-2 leads to a ↓ in apoptosis leading to an ↑ of tumorigenesis. p53 degrades Bcl-2 to promote apoptosis when DNA damage is severe extrinsic occurs in response to several external "death" signals FAS ligand binding the FAS death receptor (CD95) CD95 mediates a cascade of caspase activation via FADD, a death domain-containing adapter protein Also mediated by TNF which acts in a similar fashion to FAS killer CD8 T-cells kill virally infected cells release perforin and granzyme B which damage the cell membrane and activate caspases PD-1 and PD-L1 is a key pathway active in cancer cells Mechanism caspase cascade regulation pro-apoptotic factors Bax activated by p53 absent in Li-Fraumeni syndrome presents with high frequency of solid tumors antagonizes Bcl-2 promotes release of mitochondrial cytochrome c into the cytosol anti-apoptotic factors Bcl-2 prevents cytochrome c from being released and thus inhibits activation of caspase-9 caspases - inactive enzymes such as proteases and endonucleases activated by intrinsic and extrinsic pathways endonuclease activity leads to pyknosis (nuclear condensation) protease activity leads to cytoskeleton breakdown membrane begins to bleb containing cellular fragments apoptotic bodies break off and are phagocytosed by macrophages Key principles distinct histological changes cell shrinkage pyknosis eosinophilic cytoplasm membrane blebbing nuclear fragmentation (karyorrhexis) nuclear fading formation of apoptotic bodies lack of inflammation typically involves single or specific groups of cells leaving tissue architecture intact Examples menstrual shedding of endometrium apoptosis induced in the endometrium when estrogen and progesterone levels decrease destruction of specific cells during embyrogenesis loss of Mullerian structures in males due to Mullerian inhibititory factor virally infected cells apoptosis induced by cytotoxic T-cells embryogenesis apoptosis induced in skin between fingers