negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator. [GOC:TermGenie, PMID:17719541]

The p53 class mediator plays a crucial role in negatively regulating the intrinsic apoptotic signaling pathway in response to DNA damage. This regulation involves a complex interplay of molecular events that ultimately prevent the activation of caspases, the key executioners of apoptosis. Here's a detailed description:

1. **DNA Damage Detection and p53 Activation:** When DNA damage occurs, sensors like ATM and ATR kinases activate the tumor suppressor protein p53. p53 acts as a transcription factor, inducing the expression of various downstream genes, including pro-apoptotic proteins like Bax and Puma.

2. **p53 Mediated Inhibition of Pro-Apoptotic Protein Production:** The p53 class mediator, through its interaction with p53, can negatively regulate the expression of pro-apoptotic proteins like Bax and Puma. This inhibition can occur at multiple levels:
- **Transcriptional Repression:** The mediator might directly bind to the promoter regions of pro-apoptotic genes, blocking the access of p53 and preventing their transcription.
- **Post-Transcriptional Regulation:** The mediator might influence the stability of pro-apoptotic mRNA transcripts, promoting their degradation and reducing their translation into proteins.

3. **Activation of Anti-Apoptotic Proteins:** p53, under certain conditions, can also induce the expression of anti-apoptotic proteins like Bcl-2 and Bcl-xL. These proteins can bind to and inhibit the pro-apoptotic proteins, further reducing the apoptotic signal.

4. **Regulation of Mitochondrial Membrane Permeability:** The balance between pro-apoptotic and anti-apoptotic proteins plays a key role in regulating the permeability of the mitochondrial outer membrane. In the presence of DNA damage, p53 can promote the release of cytochrome c from mitochondria, a crucial step in the apoptotic cascade. However, the p53 class mediator can suppress this release by promoting the expression of anti-apoptotic proteins that stabilize the mitochondrial membrane.

5. **Caspase Inhibition:** The final step in apoptosis involves the activation of caspases, a family of proteases that dismantle the cell. The p53 class mediator can indirectly inhibit caspases by preventing the release of cytochrome c and promoting the expression of anti-apoptotic proteins that inhibit caspase activation.

Overall, the p53 class mediator exerts its negative regulatory effect on the intrinsic apoptotic pathway by:

- **Reducing the levels of pro-apoptotic proteins.**
- **Promoting the expression of anti-apoptotic proteins.**
- **Stabilizing the mitochondrial membrane.**
- **Indirectly inhibiting the activation of caspases.**

This fine-tuned regulation allows the cell to maintain a delicate balance between repairing DNA damage and eliminating irreversibly damaged cells, ensuring appropriate responses to DNA damage stress.'
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Proteins (9)

Compounds (821)