Apoptosis | The Extrinsic Pathway
Catalyst University・2 minutes read
The video explains the mitochondrial and extrinsic pathways of apoptosis, detailing how DNA damage activates pro-death genes and the release of apoptotic proteins, while the extrinsic pathway is initiated by immune cell interactions via the Fas receptor. It highlights that cancerous cells often bypass regulatory mechanisms, allowing for enhanced apoptosis through a cascade of events involving caspases and other signaling proteins.
Insights
- The video illustrates the critical role of mitochondria in apoptosis by highlighting how they release proteins like cytochrome c and AIF into the cytoplasm in response to DNA damage, which activates pro-death genes such as Bad, Bax, and Bak, ultimately initiating the intrinsic pathway of cell death.
- It also explains the extrinsic pathway of apoptosis, where the binding of the Fas ligand from cytotoxic lymphocytes to the Fas receptor on target cells triggers a cascade of events leading to cell death, particularly in cancerous cells that often lose the expression of inhibitors that normally prevent this process.
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Recent questions
What is apoptosis in simple terms?
Apoptosis is a programmed cell death process that occurs in multicellular organisms. It is a crucial mechanism that allows the body to eliminate damaged or unnecessary cells in a controlled manner, preventing inflammation and damage to surrounding tissues. During apoptosis, cells undergo a series of biochemical events leading to characteristic cell changes and death, including cell shrinkage, chromatin condensation, and the formation of apoptotic bodies. This process is essential for maintaining homeostasis and is involved in various physiological processes, such as development, immune response, and tissue remodeling.
How do cells know to die?
Cells receive signals that trigger apoptosis through various pathways, primarily the intrinsic and extrinsic pathways. The intrinsic pathway is activated in response to internal stressors, such as DNA damage, leading to the release of apoptotic factors from the mitochondria. Conversely, the extrinsic pathway is initiated by external signals, often from immune cells, that bind to specific receptors on the cell surface, such as the Fas receptor. These signals downregulate pro-survival genes and upregulate pro-death genes, ultimately leading to the activation of caspases, which are enzymes that execute the cell death program. This intricate signaling ensures that only cells that are damaged or no longer needed undergo apoptosis.
What triggers the intrinsic pathway of apoptosis?
The intrinsic pathway of apoptosis is primarily triggered by internal cellular stress, such as DNA damage caused by factors like UV radiation or chemical mutagens. When such damage occurs, pro-survival genes are downregulated, while pro-death genes, including Bad, Bax, and Bak, are expressed. This shift in gene expression leads to the release of apoptotic proteins, such as cytochrome c, from the mitochondria into the cytoplasm. The release of these proteins initiates a cascade of events that activate caspases, particularly caspase-9, which further propagates the apoptotic signal and leads to the systematic dismantling of the cell.
What role do caspases play in apoptosis?
Caspases are a family of cysteine proteases that play a central role in the execution of apoptosis. They exist as inactive precursors, or zymogens, and are activated in response to apoptotic signals. Initiator caspases, such as caspase-8 and caspase-9, are activated first and then cleave and activate executioner caspases, like caspase-3. Once activated, caspase-3 carries out the death program by cleaving various cellular substrates, leading to key changes associated with apoptosis, such as chromatin degradation and the formation of apoptotic bodies. This coordinated action of caspases ensures that the cell undergoes a controlled and efficient death process, minimizing damage to surrounding tissues.
How does cancer affect apoptosis?
Cancer cells often develop mechanisms to evade apoptosis, allowing them to survive and proliferate uncontrollably. One common alteration is the loss of expression of inhibitors of the Fas receptor, which is crucial for the extrinsic pathway of apoptosis. When the Fas ligand from cytotoxic lymphocytes binds to the Fas receptor on cancer cells, it can trigger apoptosis; however, if the cancer cells lack the necessary inhibitors, they become more susceptible to this signal. Additionally, cancer cells may also upregulate pro-survival signals or downregulate pro-apoptotic factors, further promoting their survival. This dysregulation of apoptosis is a hallmark of cancer and contributes to tumor growth and resistance to therapy.
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Summary
00:00
Mitochondrial and Extrinsic Pathways of Apoptosis
- The video discusses the mitochondrial pathway of apoptosis, emphasizing the mitochondria's role in releasing proteins like cytochrome c, apoptosis-inducing factor (AIF), and Diablo into the cytoplasm, which initiates apoptosis following DNA damage from sources like UV light or mutagens.
- Upon DNA damage, pro-survival genes are downregulated while pro-death genes such as Bad, Bax, and Bak are expressed, leading to the release of apoptotic proteins from the mitochondria, marking the beginning of the intrinsic pathway of apoptosis.
- The extrinsic pathway of apoptosis is introduced, which requires an external stimulus, typically from immune cells, and involves the Fas receptor, a constitutively expressed transmembrane protein on all cells that can trigger cell death.
- The Fas receptor interacts with Fas-associated death domains (FADD) and inactive zymogen pro-caspase-8, which must be activated to execute apoptosis; however, inhibitors present in healthy cells prevent this activation.
- Cancerous cells often lose the expression of Fas receptor inhibitors, allowing the Fas ligand from cytotoxic lymphocytes (CD8+ cells) to bind to the Fas receptor, leading to receptor activation and subsequent activation of pro-caspase-8.
- Activated caspase-8, an initiator caspase, can convert pro-caspase-3 into active caspase-3, which executes apoptosis by cleaving substrates, leading to chromatin degradation, proteolysis, and the formation of apoptotic bodies.
- Caspase-3 can activate other executioner caspases and is involved in the degradation of the inhibitor of apoptosis (IAP), further promoting cell death.
- Caspase-8 also activates Bid, which is similar to pro-death proteins like Bad, Bax, and Bak, facilitating the release of apoptotic factors from the mitochondria and linking the extrinsic pathway to the intrinsic pathway.
- The accumulation of tBid, the active form of Bid, can lead to the activation of caspase-9 and the formation of the apoptosome, which further propagates the apoptotic signal.
- The extrinsic pathway is primarily activated by cancerous cells that stop expressing Fas receptor inhibitors, allowing for complete apoptosis through the interaction of Fas ligand and receptor, leading to a cascade of apoptotic events.
16:05
Mechanism of CD8 Cell-Induced Apoptosis
- The process of apoptosis is induced when a cytotoxic lymphocyte, specifically a CD8 positive cell, binds to the Fas ligand on a target cell, which is a normal somatic cell expressing MHC class I proteins; in cancerous cells, these MHC class I proteins often present abnormal antigens, allowing the CD8 receptor on the CD8 positive cell to bind and trigger cell death, with additional interactions and inhibitors enhancing this process.
