Name: how cells trigger apoptosis from damage
Uploaded: 2023-04-30T10:28:19.000Z
Duration: 1 min 31 s
Channel: JoVE

The intrinsic apoptotic pathway is activated by intracellular death signals, such as oxidative stress and DNA damage.
In mammals, the pathway is regulated by the Bcl-2 family of proteins, which has both pro- and anti-apoptotic family members.
Proapoptotic proteins include BH3-only&#160; proteins, such as Bad and Bim, and effector Bcl-2 family proteins, such as Bax and Bak.&#160; Anti-apoptotic proteins&#160; include Bcl-XL and Bcl-2&#160; and inhibit Bax and Bak activity.
Death signals activate the BH3-only proteins, which can either inactivate anti-apoptotic proteins or directly bind to effector proteins.
In either case, these effectors oligomerize on the mitochondrial membrane and form pores that release cytochrome c.
Cytochrome c binds to apoptotic protease activating factor-1, Apaf-1, and&#160; Apaf-1 monomers then assemble into a heptameric complex, called the apoptosome.

Next, the initiator procaspase-9 binds to the apoptosome and dimerizes, forming caspase-9.
Finally, caspase-9 activates the executioner caspases that cleave cellular proteins, resulting in apoptosis.

the intrinsic apoptotic pathway

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits anti-apoptotic proteins Bcl-2, Bcl-XL, and survivin. This whole chain of events eventually leads to apoptosis of the damaged cells.
<h4>Cancer and the Intrinsic Apoptotic Pathway</h4>
The intrinsic pathway is inhibited during cancer due to mutations in pro-apoptotic and anti-apoptotic proteins. For example, in melanoma, the overexpressed inhibitor of apoptosis proteins or IAPs causes the inactivation of caspase-9, preventing apoptosis. In most cancer cells, Bcl-2, an anti-apoptotic protein first found in follicular lymphoma, is overexpressed.
Several anti-cancer drugs that can activate the intrinsic apoptotic pathway have been developed. For example, molecules such as Nultlin-2 and MI-219 inhibit the binding of MDM2 to p53, thereby preventing the inactivation of p53 and leading to apoptosis of cancerous cells. Some drug molecules, such as SH122, JP1201, and YM155, inhibit IAPs and help activate caspases, thereby initiating apoptosis in cancer cells.

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the ...

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JoVE Core

Cell Biology

Unit 1

Cell Death

KEY TERMS AND CONCEPTS

how cells trigger apoptosis from damage

Intrinsic apoptosis is the cell’s built-in death response to internal stress. Cell injury, hypoxia, and DNA damage can start this process. The B-cell lymphoma 2, or Bcl-2, family of proteins is the main regulator of this pathway.

When DNA is damaged, checkpoint proteins such as Ataxia Telangiectasia Mutated, or ATM, and Checkpoints Factor-2, or Chk2, become active. They phosphorylate p53, a protein that helps control cell survival. p53 then turns on pro-apoptotic proteins such as Bax, Bak, PUMA, and Noxa. At the same time, it blocks anti-apoptotic proteins such as Bcl-2, Bcl-XL, and survivin.

These changes push the damaged cell toward apoptosis, or programmed cell death. In cancer, this pathway is often blocked by mutations in proteins that promote or prevent apoptosis. For example, in melanoma, overexpressed inhibitor of apoptosis proteins, or IAPs, inactivate caspase-9 and stop apoptosis. In many cancer cells, Bcl-2 is also overexpressed. It was first identified in follicular lymphoma.

Some anti-cancer drugs are designed to reactivate the intrinsic apoptotic pathway. Nultlin-2 and MI-219 block the binding of MDM2 to p53. This helps keep p53 active and can lead to death of cancer cells. Other drugs, including SH122, JP1201, and YM155, inhibit IAPs and help activate caspases, which start apoptosis.

How Cells Trigger Apoptosis from Damage

overview of cell death

Cell Death Pathways in Cells

Cell death pathways help the body remove old or damaged cells. Cell growth and cell death must stay balanced. If this balance is disrupted, it may contribute to cancer or autoimmune diseases. Cell death was first noticed in the early 19th century, but experimental proof came later. In 1842, Carl Vogt described cell death in a metamorphic toad. At that time, the process was not yet called cell death. Scientists identified separate cell death pathways in the 20th century after advances in...

apoptosis

Apoptosis and Cell Survival Control

Apoptosis is a controlled form of cell death that helps keep tissues healthy. The term comes from two Greek words, apo and ptosis, which mean separation and falling off. Hippocrates used the word to describe gangrene caused by bandaging fractured bones. Apoptosis was separated from necrosis in 1970 after John Kerr described its distinct shape changes. In one experiment, loss of blood supply to liver tissue caused the tissue to shrink. Under an electron microscope, Kerr saw that hepatocytes had...

caspases

Caspases in Apoptosis and Immunity

Caspases are cysteine proteases that help control cell death and immune defense. They act as effectors in apoptosis, which is the process of programmed cell death. The ced-3 gene in C. elegans was first linked to apoptosis, and it encodes a caspase similar to the interleukin-1-beta converting enzyme, or ICE, in mammals. Caspases also have a role in inflammation. Inflammatory caspases activate pro-inflammatory cytokines, which help recruit immune cells and stop pathogens from replicating inside...

the extrinsic apoptotic pathway

How Immune Cells Trigger Cell Death

The extrinsic apoptotic pathway is a cell death process started by signals from outside the cell. In this pathway, extracellular death signals such as specific cytokines activate death receptors on the cell surface. Natural killer cells, or NK cells, and cytotoxic T-lymphocytes help carry out this response. NK cells are part of the innate immune response, while cytotoxic T-lymphocytes belong to the adaptive immune response. These cells recognize receptors on altered cells and activate...

Intrinsic apoptosis is the cell’s built-in death response to internal stress. Cell injury, hypoxia, and DNA damage can start this process. The B-cell lymphoma 2, or Bcl-2, family of proteins is the main regulator of this pathway. When DNA is damaged, checkpoint proteins such as Ataxia Telangiectasia Mutated, or ATM, and Checkpoints Factor-2, or Chk2, become active. They phosphorylate p53, a protein that helps control cell survival. p53 then turns on pro-apoptotic proteins such as Bax, Bak,...

phagocytosis of apoptotic cells

How Apoptotic Cells Are Cleared

Apoptotic cells must be cleared quickly so they do not cause inflammation, autoimmune disease, or necrosis. During apoptosis, cells break into apoptotic bodies that are then removed by phagocytosis, the process in which other cells engulf and digest them. Professional phagocytes, such as macrophages and immature dendritic cells, handle this job most effectively. Some non-professional phagocytes, including epithelial cells and fibroblasts, can also take part, but they are less efficient. Normal...

autophagic cell death

Autophagy and Cell Death Pathways

Autophagy is a cell cleanup process that can also lead to cell death. Christian de Duve discovered autophagy, in which cell parts are enclosed in membrane-bound sacs called autophagosomes. These autophagosomes then fuse with lysosomes, which digest the material inside. In many cells, autophagy helps prevent cell death. When damage becomes too severe to repair, however, the process can shift toward cell death. Autophagy can connect to apoptosis, necroptosis, and autosis, so it sits at an...

necrosis

Necrosis and Other Cell Death Pathways

Necrosis is an accidental form of cell death that ends in cell lysis, or cell bursting. Rudolf Virchow first used the term in 1859 in his book Cell Pathology to describe advanced tissue breakdown. In high school biology, necrosis is often used to compare damaged cells with other ways cells can die. Necrotic cells can look different depending on the tissue and the cause of injury. In coagulative necrosis, cells lose their nuclei but keep their basic shape because the enzymes that digest cell...

key terms and concepts

Learn how internal cell stress, DNA damage, p53, Bcl-2 proteins, and cancer drugs control intrinsic apoptosis and programmed cell death.

How Cells Trigger Apoptosis from Damage | JoVE K12

cell biology

JoVE Core Cell Biology illustrates complex cellular processes in easy-to-understand yet comprehensive animated video lessons. This collection focuses on the essential components and functions of cells, including organelles and membranes, cellular transport, and cell energetics. It is complemented by scientist-in-action videos that demonstrate the application of cell biology in real-world research experiments.

How Cells Trigger Apoptosis from Damage

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