Medical Biochemistry: Apoptosis, Programmed Cell Death

I just dig all the science words... and considering the mechanisms of nature... it sure is some curious and amazing stuff !!!

Figure 32.1. Scheme of the factors involved in the apoptotic process.

APAF-1, Apoptosis protease activator factor-1; Bak, Bcl-associated antagonist killer; Bax, Bcl-associated X protein; Bcl-2, B cell lymphoma-2; DD, death domain; DED, death effector domain; IAP, inhibitor apoptosis protein; TNFR, tumor necrosis factor receptor; TRADD, TNFR-associated death domain.

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Programmed Cell Death

In Cell Biology (Third Edition), 2017

Excess Cells

Programmed cell death is also widely used for quality control during development.

For example, in the brain,

embryonic ganglia often have many more neurons than are required to enervate their target muscles. Production of excess cells is part of a {...} strategy to ensure that a sufficient number of axons reach their targets.

Programmed cell death eliminates excess neurons that fail to make appropriate connections. Up to 80% of neurons in certain developing ganglia die in this way.

... ~ surf onward ~*~ sample of recently published research in the topic(s) ~~~~~~~~

Apoptosis

Antonio Blanco, Gustavo Blanco, in Medical Biochemistry, 2017

Intrinsic or mitochondrial pathway

Apoptosis can be activated by stimuli coming within the cell, including cell stressors, such as hypoxia or lack of nutrients, and agents that cause damage of DNA or other cell structures. In vertebrates this pathway is initiated by the release of apoptosis mediators from the mitochondrial intermembrane space, when certain intracellular signals permeabilize the outer membrane of the mitochondria.

A major protein in this process is cytochrome c, component of the electron transport chain on the external face of the inner mitochondrial membrane. When released into the cytosol, cytochrome c binds to APAF-1, which oligomerizes to form a complex or apoptosome. Once formed this complex, comprising APAF-1–cytochrome c–procaspase 9, triggers the activation of procaspase 9 to caspase 9. This initiator protease starts the hydrolytic cascade that stimulates the effector caspases (3, 6, and 7).

In addition to cytochrome c, other molecules are released from mitochondria. These include Diablo or second mitochondria-derived activator of caspases (SMAC), which by blocking inhibitor of apoptosis proteins induces programmed cell death; Omi, which is a stress-regulated endoprotease that activates caspases; and endonuclease G, which is responsible for DNA degradation, chromatin condensation, and DNA fragmentation.

Other apoptotic pathways. A third pathway leading to apoptosis is specific of cytotoxic T lymphocytes (CTL) and natural killer cells (NK) (Chapter 30). A serine protease designated granzyme B (Gra-B) functions as caspases, hydrolyzing peptide bonds at aspartate residues. Gra-B enters the cells through channels formed by perforin. Gra-B also activates procaspases 3 and 10 and can stimulate the mitochondrial pathway.

A fourth pathway for caspase activation is triggered by cell organelle–mediated cell death. Apoptosis can be initiated by stressors that affect the integrity of the nucleus, endoplasmic reticulum, Golgi, and lysosomes.

Regulation of apoptosis. Due to the irreversible consequence of apoptosis, both the intrinsic and extrinsic pathways are under tight control. The major regulator of apoptosis is the Bcl (from B cell lymphoma) family of proteins. The members of this group of proteins include proapoptotic and antiapoptotic agents, which control the release of cytochrome c and other mitochondrial proteins to the cytosol, regulating downstream caspase activation. The Bcl family of proteins have BH (Bcl-2 homology) domains, which gave them the designation BH1234. Bcl-2 has four BH domains and was initially identified as a protein encoded by the oncogene that stimulates the development of B cells lymphomas. Unlike other oncogenes, such as Ras, that stimulate cell proliferation, Bcl-2 is an inhibitor of programmed cell death, promoting the survival of cancer cells, which continue their uncontrolled growth. Other Bcl proteins with antiapoptotic function are Bcl-xL, Bcl-W, and other proteins that contain BH1234 homologous domains.

Not all the members of the Bcl family of proteins are antiapoptotic. Bcl-2 associated X protein (Bax) and Bcl-2 antagonist killer (Bak) have three BH domains instead of four (designated BH123). They promote programmed cell death. When the intrinsic pathway is activated, Bax and Bak form oligomers on the cytosolic side of the outer mitochondrial membrane, creating pores that permeabilize the mitochondrial membrane, allowing the release of cytochrome c and other intermembrane proapoptotic proteins, including Diablo and Omi, to the cytosol.

The fate of a cell depends on the balance between pro- and antiapoptotic proteins, which antagonize each other. Bcl-2 interferes with Bax and Bak proteins, disrupting the balance in favor of cell survival.

The intrinsic and extrinsic pathways are both regulated by the apoptosis inhibitor protein (IAP). IAP directly interacts with caspases and suppresses apoptosis either by inhibiting them, or labeling them for ubiquitination and subsequent degradation in the proteasome (p. 368). The Diablo and Omi proteins released from the intermembrane space, are proapoptotic. Diablo opposes to Bcl and Omi stimulates caspase activity by interfering the action of AIP. Fig. 32.1 is a scheme of the factors involved in apoptosis.

An important function of programmed cell death

is the elimination of damaged cells,

especially those that have undergone changes in their DNA.

These cells are dangerous as they can accumulate mutations and become carcinogenic.

Many neoplastic cells show an upregulation of the expression of antiapoptotic members of the Bcl-2 family. In mammalian cells there are mechanisms that prevent malignant transformation of cells. In response to DNA damage, these mechanisms are mediated by the transcription factor of p53 (tumor suppressor protein) that induces expression of cyclin inhibitors and stops cell cycle progression. In addition to this action, p53 also triggers apoptosis by inducing expression of protein BH3 of the intrinsic pathway.

Medical importance.

Many diseases are associated with disturbances in the regulation of apoptosis.

For example,

in Alzheimer’s disease and other neurodegenerative diseases, abnormal apoptosis leads to exacerbated neuronal destruction in specific regions of the brain.
There is also increased apoptotic activity in T lymphocytes in the acquired immunodeficiency syndrome (AIDS).

Other examples of increased cell destruction are heart attacks and strokes.

In these cases, the necrosis resulting from the lack of oxygen supply predominates, but some cells affected by hypoxia undergo apoptosis. It is expected that the development of caspase inhibitor drugs will be useful in these conditions.

Mutations in the genes encoding factors associated with programmed cell death result in serious alterations.

A failure of the gene that directs the synthesis of Fas death receptors, reduces cell removal, leading to cell accumulation in spleen and lymph nodes, which is a cause of autoimmune diseases.

Elimination of unwanted cells is impaired in some types of tumors.

In lymphoma, there is a chromosomal translocation that determines excessive production of Bcl-2 protein and inhibition of apoptosis. In 50% of human cancers, mutations in the p53 gene have been shown. Some of the drugs used in the treatment of neoplasias induce apoptosis and cell cycle arrest by a mechanism dependent on p53. In cases in which the p53 gene is mutated, the cancer cells are not sensitive to chemotherapy.

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