intrinsic apoptotic signaling pathway in response to osmotic stress by p53 class mediator

Definition

Target type: biologicalprocess

The series of molecular signals in which an intracellular signal is conveyed to trigger the apoptotic death of a cell. The pathway is induced by the cell cycle regulator phosphoprotein p53, or an equivalent protein, in response to the detection of osmotic stress, and ends when the execution phase of apoptosis is triggered. [GOC:krc, GOC:mtg_apoptosis, PMID:16571598]

The intrinsic apoptotic signaling pathway, also known as the mitochondrial pathway, is a crucial mechanism for programmed cell death in response to various stressors, including osmotic stress. In the context of osmotic stress, the tumor suppressor protein p53 plays a significant role as a class mediator, orchestrating the activation of this pathway. Here's a detailed breakdown of the process:

1. **Osmotic Stress Detection:** When cells experience osmotic stress, such as a sudden shift in extracellular tonicity, they sense the imbalance through mechanosensitive channels and other cellular sensors. This triggers signaling cascades that ultimately activate the p53 pathway.

2. **p53 Activation:** p53, a transcription factor, is normally kept in check by its negative regulators. However, under stress conditions, these regulators are inactivated, allowing p53 to become activated. Activated p53 then translocates to the nucleus and acts as a transcription factor, upregulating the expression of various pro-apoptotic genes, including:

* **Bax and Bak:** These proteins are pro-apoptotic members of the Bcl-2 family. Their upregulation leads to the formation of pores in the outer mitochondrial membrane.
* **Puma and Noxa:** These are BH3-only proteins that activate Bax and Bak, further promoting the formation of mitochondrial pores.
* **Apaf-1:** Apoptotic protease activating factor-1, is a crucial component of the apoptosome, a multi-protein complex that activates caspase-9.

3. **Mitochondrial Permeabilization:** The increased expression of Bax and Bak proteins leads to the formation of pores in the outer mitochondrial membrane. This event, known as mitochondrial outer membrane permeabilization (MOMP), allows the release of cytochrome c and other pro-apoptotic factors from the intermembrane space into the cytosol.

4. **Apoptosome Formation:** Cytochrome c released from mitochondria binds to Apaf-1, which in turn recruits pro-caspase-9. This complex, known as the apoptosome, activates caspase-9.

5. **Caspase Cascade Activation:** Caspase-9, an initiator caspase, activates downstream executioner caspases, such as caspase-3 and -7. These caspases then cleave and activate various cellular substrates, leading to the characteristic features of apoptosis.

6. **Apoptotic Cell Death:** The activation of executioner caspases results in a cascade of events, including:

* DNA fragmentation: Caspases cleave DNA into fragments, leading to the characteristic "ladder" pattern observed in apoptotic cells.
* Cell shrinkage: Caspases also cleave cytoskeletal proteins, leading to cell shrinkage and blebbing.
* Formation of apoptotic bodies: Ultimately, the apoptotic cell breaks down into small membrane-enclosed fragments called apoptotic bodies, which are phagocytosed by neighboring cells or macrophages.

In summary, the intrinsic apoptotic pathway in response to osmotic stress, mediated by p53, is a carefully orchestrated cascade of events involving mitochondrial membrane permeabilization, apoptosome formation, caspase activation, and ultimately the dismantling of the cell into apoptotic bodies. This process is essential for maintaining cellular homeostasis and eliminating damaged or stressed cells, contributing to tissue repair and preventing uncontrolled cell growth.'
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Proteins (1)

Compounds (13)