17. Apoptosis

examples of dysfunctions of apoptosis? (when apoptosis is not functioning properly)

cancer, autoimmune diseases, viral infections, neurodegenerative disorders, acquired immune deficiency syndrome (AIDs), ischemic diseases

describe the necrotic mode of cell death

in contrast to apoptosis, in the necrotic mode of cell-death the cells suffer a major insult, resulting in a loss of membrane integrity, swelling and disrupture of the cells, during necrosis, the cellular contents are released uncontrolled into the cells environment, which results in damage of surrounding cells and a strong inflammatory response in the corresponding tissue

what is the definition of apoptosis?

morphological processes leading to controlled cellular self-destruction (cell death)

premature death of cells and living tissue? while apoptosis often provides beneficial effects to the organism, this process is almost always detrimental and can be fatal.

necrosis

how do you control apoptosis?

the Bcl-2 family members are decision makers that integrate prodeath and antideath signals to determine whether the cell should commit suicide. (members: anti-apoptotic, and pro-apoptotic)

what are 2 regulators of apoptosis?

1. Bcl-2 family 2. IAP (inhibitor of apoptosis) family

what are the apoptotic signaling pathways?

1. caspase 2. intrinsic apoptosis pathway 3. extrinsic apoptosis pathway

what are some examples of apoptosis?

1. formation of free and independent digits by massive apoptosis in the interdigital mesenchymal tissue 2. development of the brain, during which half of the neurons that are created will die in later stages when the adult brain is formed 3. development of the reproductive organs (male/female) 4. maintenance of homeostasis of an adult organisms--cell proliferation must be balanced with cell death in order to maintain constant cell numbers 5. function of the immune system 6. removal of defect and therefore harmful cells dysfunction or dysregulation of the apoptotic program

caspases are cysteine proteases that cleave peptide bonds next to an aspartate residue, and are synthesized as inactive pro-caspases. what are 2 types of caspases?

1. initiator caspases: cleave other procaspases 2. effector caspases: cleave other cellular proteins involved in maintaining cellular integrity

what are 2 pathways that initiate apoptosis?

1. intrinsic: mitochondiral apoptosis 2. extrinsic: death receptor apoptosis **these pathways intersect at the effector caspases

what triggers apoptosis?

1.withdrawal of positive signals: the cont. survival of most cells requires that they receive cont. stimulation from other cells. ex: physical contact with other cells, trophic factors (ex: physical contact with other cells, trophic factors) 2. receipt of negative signals: increased levels of oxidants within the cell, damage to DNA by these oxidants or by other agents like UV light, x-rays, chemotherapeutic drugs, accumulation of proteins that failed to fold properly into their proper tertiary structure, molecules that bind to specific receptors on the cell surface and signal the cell to begin the apoptosis program. these death activators include: tumor necrosis factor-alpha, Fas ligand

describe the morphological features of apoptosis.

Apoptotic cells can be recognized by stereotypical morphological changes: Cell shrinkage and rounding are shown because of the breakdown of the proteinaceous cytoskeleton by caspases. The cytoplasm appears dense, and the organelles appear tightly packed. Chromatin undergoes condensation into compact in a process known as pyknosis. The nuclear envelope becomes discontinuous and the DNA is fragmented in a process referred to as karyorrhexis. The nucleus breaks due to the degradation of DNA. The cell membrane shows irregular buds known as blebs. The cell breaks apart into several vesicles called apoptotic bodies, which are engulfed by macrophages and thus are removed from the tissue without causing an inflammatory response. Dying cells that undergo the final stages of apoptosis display phagocytotic molecules, such as phosphatidylserine, on their cell surface. Phosphatidylserine is normally found on the cytosolic surface of the plasma membrane, but is redistributed during apoptosis to the extracellular surface.

describe activation of apoptosis from the inside of the cell: intrinsic pathway

Apoptotic stimuli trigger the release of apoptogenic factors from the mitochondrial intermembrane space to the cytosol, such as cytochrome c. Cytochrome c binds with Apoptotic protease activating factor - 1 (Apaf-1) and create a protein complex known as an apoptosome. The apoptosome recruits and cleaves pro-caspase-9 to its active form of caspase-9, which in turn activates the effector caspase-3 leading to proteolytical degradation of intracellular proteins to carry out the cell death program.

describe activation of apoptosis from outside of the cell: extrinsic apoptosis pathway

Death Receptors belong to the Tumor Necrosis Factor Receptor (TNFR) gene superfamily. Upon ligation by its cognate ligand, the oligomerized death receptor recruits adaptor molecules via its cytoplasmic death domains (DD). Besides possessing DDs, the adaptors additionally contain death effector domains (DED) which recruit procaspase-8 to the receptor complex, which now is called the death-inducing signaling complex (DISC). Procaspase-8 is activated by autoproteolytic cleavage and forms the active caspase-8. The initiator caspase-8 cleaves and activates executioner caspases for the execution of apoptosis.

describe regulation of apoptosis by Bcl-2 family

Some members of this family of intracellular proteins like Bcl-2 itself or Bcl-XL, inhibit apoptosis, at least partly by blocking the release of cytochrome c from mitochondria. Other members of the Bcl-2 family are not death inhibitors, but instead promote apoptosis. Some of these regulstors, such as Bad, function by binding to and inactivating the death-inhibiting members of the family, whereas others, like Bax and Bak, stimulate the release of cytochrome c from mitochondria. Bax and Bak are themselves activated by other apoptosis-promoting members of the Bcl-2 family such as Bid.

describe the apoptotic signaling pathway: caspase

The caspases, cysteine-dependent aspartate-directed proteases, are of central importance in the apoptotic signaling network. Caspases are synthesized as inactive zymogens, the so called procaspases. The proapoptotic caspases can be divided into two groups; initiator caspases (caspases-2, -8, -9 and -10) and executioner caspases (caspases-3, -6, and -7).

describe regulation of apoptosis by IAP family

These proteins are thought to inhibit apoptosis in two ways: they bind to some procaspases to prevent their activation, and they bind to caspases to inhibit their activity. When mitochondria release cytochrome c to activate Apaf-1, they also release a protein that blocks IAPs, thereby greatly increasing the efficiency of the death activation process.

duirng apoptosis, the cell breaks apart into several vesicles called ___ which are engulfed by macrophages and thus are removed from the tissue without causing an inflammatory response. dying cells that undergo the final stages of apoptosis display phagocytotic molecules, such as phosphatidylserine, on their cell surface. phosphatidylserine is normally found on the cytosolic surface of the plasma membrane, but it is redistributed during apoptosis to the extracellular surface.

apoptotic bodies

morphological features of apoptosis

apoptotic cells can be recognized by stereotypical morphological changes: cell shrinkage and rounding are shown because of the breakdown of the proteinaceous cytoskeleton by caspases

cells that undergo apoptosis display an "EAT ME" signal to elicit phagocytosis. What is the signal of the inner leaflet of the cell membrane? Apoptotic cells flip this signal to the outside of the leaflet to let the phagocytes scavengers recognize the signal

phosphatidylserine (PS)

what is the significance of apoptosis?

plays an important role in the development of multicultural organisms and in the regulation and maintenance of the cell populations in tissues upon physiological and pathological conditions

during apoptosis, the cytoplasm appears dense, and the organelles appear tightly packed. chromatin undergoes condensation and compacts in a process known as? and the cell membrane shows irregular buds known as?

pyknosis blebs

the deletion of damaged and dangerous cells is significant because?

these cells have severely damaged DNA which will replicate