Module 44: Cell Senescence and Death PDF

Module 44: Cell Senescence and Death Cellular Senescence Senescent cells: no longer divide are still metabolically active with immunogenic phenotype express senescence-associated beta-galactosidase typically, are larger and have a characteristic flattened appearance the nucleus has senes...

Module 44: Cell Senescence and Death Cellular Senescence Senescent cells: no longer divide are still metabolically active with immunogenic phenotype express senescence-associated beta-galactosidase typically, are larger and have a characteristic flattened appearance the nucleus has senescence-associated heterochromatin foci (SAHF) with changes in gene expression with senescence-associated secretory phenotype, including inflammatory cytokines. Senescence: Mechanisms and Consequences Fibroblasts in culture become senescent after ~ 50 divisions, i.e., “replicative senescence” — the Hayflick limit Replicative senescence results from telomere shortening and consequent DNA damage responses Senescence can also occur independently of telomere shortening as a result of oxidative damage, oncogenes, or cell fusion Senescent cells increase with age Senescence may have evolved as an anti-cancer mechanism Whereas cellular senescence in younger organisms is anti-tumorigenic, it may be pro-tumorigenic in older organisms Senescence-associated secretory phenotype is associated with age-related diseases Senolytic therapy: kill and eliminate senescent cells to improve the health of older organisms In mice, the removal of senescent cells improves health and extends the lifespan Apoptosis: Introduction Programmed cell death: regulated, orderly process Molecular/biochemical events lead to cell blebbing, shrinkage, nuclear fragmentation, chromatin condensation, DNA fragmentation, mRNA decay Billions of human cells undergo apoptosis daily: part of the normal homeostasis of tissues Can be deregulated in disease (too much or too little) Two pathways: intrinsic (cell senses stress, induces apoptosis) and extrinsic (cell responds to outside signals that induce apoptosis) Both pathways activate proteases called caspases Initiator caspases start the “caspase cascade” and executioner caspases perform the terminal steps Caspase-independent apoptosis possible (apoptosis-inducing factor or AIF) Basic Control of Apoptotic Pathways Pathway Steps Pathway Steps Intrinsic Mediated through mitochondria Deactivation of proteins that inhibit apoptosis (IAPs) Cytochrome C is released from mitochondria and binds to factors to form the apoptosome Caspase 9 is activated and, in turn, activates the executioner caspase 3 Extrinsic TNF-induced or Fas-Fas ligand-mediated Factors such as TNF-alpha or Fas bind to receptors, forming death-inducing signaling complexes with TRADD and FADD Activation of caspase 8 (and other caspases) begins the cascade Caspase Cascade Initiating and executioner caspases for intrinsic and extrinsic pathways shown in the diagram (learn the pathways!) Initiating caspases activate the executioner caspases Executioner caspases are responsible for the degradation of cellular macromolecules that cause cell death BCL-2 Family of Apoptotic Factor Proteins Important modulators of apoptosis Either pro-apoptotic or anti-apoptotic types (see diagram at left) Contain Bcl-2 homology (BH) domains that are critical for function Localized to the outer mitochondrial membrane Membrane of animal cells typically exerts their effects through mitochondrial-mediated apoptotic steps Apoptosis and Disease Deregulation of apoptosis can cause disease Too little apoptosis can promote cancer (e.g., loss of the p53 tumor suppressor can cause reduced apoptosis), inflammatory diseases, autoimmune syndromes, and infections Too much apoptosis can cause neurodegenerative diseases (loss of neurons) Therapeutics can be aimed at promoting or suppressing apoptosis as needed Necrosis Typically, non-apoptotic cell death (but can occur after apoptosis) From external factors: infection, toxins, trauma to cell Receptor activation, followed by loss of cell membrane integrity Typically, DNA is degraded, the nucleus shrinks, fragments, and disperses Necrosis is almost always harmful to the organism, with an inflammatory response, and damage to surrounding tissue (e.g., gangrene) Putting It Together Senescence, apoptosis, and necrosis all stop the replicative life of the cell, but do so in different ways, with varying consequences to the cell and organism Senescence can be replicative or induced; senescent cells do not divide but are metabolically active and have a distinct phenotype Apoptosis is a tightly controlled cell death process that can occur via an intrinsic or extrinsic pathway BCL-2 proteins are important modulators of apoptosis Necrosis is typically detrimental non-apoptotic cell death resulting from cell stress Apoptosis is a normal part of tissue homeostasis but can become deregulated in disease