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Apoptosis

Apoptosis is a natural and programmed form of cell death that occurs in multicellular organisms. It was first described in 1842 and distinguished from necrosis in 1965. During apoptosis, a series of biochemical events lead to changes in the cell and its death, allowing it to be eliminated in a controlled way that does not cause inflammation. This process is regulated by complex signaling pathways within the cell and involves mitochondria, caspases and other components. Defects in apoptosis can result in cancer if cell death is inhibited or neurodegenerative diseases if cell death is excessive.

Health & Medicine◦Technology◦
By Michael A. Medez
APOPTOSIS • First described by Carl Vogt in 1842 • 1965, distinguished from necrosis • Greek word “falling off” • Programmed Cell Death • Biochemical reactions lead to cell changes and death • Around 50 to 70 billion cells die each day due to apoptosis
APOPTOSIS vs NECROSIS • Apoptosis • Necrosis  Natural Cell Death  Traumatic Cell Death  Stimulated by cell signals  Stimulated by factors  Beneficial external to the cells  Produces cell fragments that  Fatal are able to send signals that  Cannot send signals, leads to facilitate phagocytosis build up of dead tissue and cell debris
PROCESS • Controlled by a diverse range of cell signals  Extracellular (Extrinsic Inducers) • Toxins, hormones, cytokines • Positive Induction or Negative Induction  Intracellular (Intrinsic Inducers) • Initiates in response to stress (heat, radiation, hypoxia, nutrient deprivation)
REGULATION • Mitochondrial Regulation  Mitochondria is essential to cell life  Exploited by apoptotic pathways  Cause mitochondrial swelling or may increase the permeability of the membrane • Direct Signal Transduction  TNF (Tumor Necrotic Factor) Pathway  Fas Pathway
TNF and Fas  TNF Pathway • Fas Pathway  TNF is a cytokine produced  Binds the Fas Ligand by macrophages  Formation of Death  Major extrinsic mediator of Inducing Signaling Complex apoptosis (DISC)  Leads to caspase activation  Caspase activation via the via membrane proteins FADD TRADD and FADD  Indirectly leads to activation of transcription factors involved in cell survival and inflammatory response
COMPONENTS • Following activation of TNF and Fas, a balance between proapoptotic and anti-apoptotic members of the Bcl-2 family is established • Proportion of proapoptotic homodimers that form in the outer membrane of the mitochondria, required to make the membrane permeable for the release of caspase activators
CASPASES • Cysteine-dependent aspartate-secific proteases • Play a central role in transduction of apoptopic signals • Highly conserved proteins • Intiator Caspases  Activates by binding to specific oligomeric adaptor protein • Effector Caspases  Activated by active initiator caspases through proteolytic cleavage  Degrade intracellular proteins to carry out cell death program
MECHANISM 1. Cell receives stimulus 2. Shrinks (breakdown of cytoskeleton) 3. Dense cytoplasm, packing of organelles 4. Condensation of chromatin (PYKNOSIS) 5. Fragmentation of DNA, breaking of nucleus 6. Formation of blebs 7. Cell breaks, formation of apoptotic bodies 8. Phagocytosis
REMOVAL OF DEAD CELLS • Efferocytosis • Dying cells display phagocytotic molecules, phosphatidylserine • Mark the cell for phagocytosis
DEFECTS in APOPTOSIS • p53  Tumor suppressor protein  Accumulates when DNA is damaged  Prevents the cell fro replicating to give it time to repair  Induce apoptosis if damage is extensive and repair efforts fail  Any disruption to its regulation results in impaired apoptosis and possible formation of tumors
INHIBITION and HYPERACTIVITY • INHIBITION • HYPERACTIVITY  Decrease in cell  Loss of control of cell death death  Most common is  HIV CANCER