How is the p53 protein activated?

The p53 protein is a tumour suppressor that remains inactive under normal cell conditions. Its activation is carefully regulated and occurs only when the cell experiences stress, especially DNA damage. This activation helps the cell decide whether to pause the cycle for repair or undergo apoptosis. The process of activation mainly depends on blocking its negative regulator and allowing p53 to become stable and active.

Mechanism of p53 Activation

The activation of p53 happens mainly in response to DNA damage, oxidative stress, hypoxia, or oncogene activation. The steps involved are:

Step 1: Detection of DNA Damage

  • When DNA is damaged due to UV rays, radiation, chemicals, or errors during replication, special sensor proteins such as ATM (Ataxia Telangiectasia Mutated) and ATR (ATM and Rad3-related) are activated. These proteins sense the damage and initiate a signalling cascade.

Step 2: Activation of Checkpoint Kinases

  • ATM and ATR then activate downstream proteins like Chk1 and Chk2 (checkpoint kinases). These kinases phosphorylate specific target proteins that regulate the cell cycle and DNA repair, especially the p53 protein.

Step 3: Phosphorylation of p53 and MDM2

  • These checkpoint kinases phosphorylate p53 at specific serine residues (like Ser15 and Ser20). This phosphorylation changes the structure of p53 and prevents it from binding with MDM2, a protein that normally adds ubiquitin to p53 for degradation. MDM2 itself can also be phosphorylated, reducing its activity. As a result, p53 becomes stable and starts to accumulate in the nucleus.

Step 4: Stabilisation and Nuclear Accumulation of p53

  • Now free from MDM2 control, p53 protein accumulates in the nucleus in its active form. It becomes a transcription factor, which means it can now bind to DNA and start the expression of specific genes.

Step 5: Transcription of Target Genes

  • The activated p53 turns on many important genes such as:
    • p21 (Cip1): Stops the cell cycle by inhibiting CDKs
    • GADD45: Involved in DNA repair
    • BAX, PUMA, NOXA: Involved in apoptosis if damage is not repairable



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