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P53

p53 is a transcription factor that normally has a very short half-life; in response to dsDNA damage (due to radiation, for example) it stabilizes, activates and promotes transcription of certain genes by binding their control regions.

p53 is activated in response to DNA damage and DNA virus infection, and it is a significant tumor suppressor. Since it is mutant in so many tumors and normal in most healthy tissues, p53 is considered the most important tumor suppressor (another important tumor suppressor is retinoblastoma). p53 inducers and mtuant phenotypes are:

p53 InducerResult of mutation
DNA DamageMutagen sensitivity
Abnormal ProliferationReduced apoptosis
Telomere ErosionOvercome senescence
Angiogenesis (blood vessels)Decreased death, increased tumor size
Loss of physical tumor containmentMetastasis (spread to other tissues)
ChemoresistenceGrim therapeutic diagnosis

DNA damage

Low DamageAt low levels of DNA damage, P53 activates transcription of gene for p21CIP, a protein that binds to and inhibits Cdk-Cyclin protein kinases to inhibit passage through cell cycle until DNA damage is repaired. As a result, cells are unable to enter S-phase until DNA damage is repaired and P53 activation diminishes.
High DamageAt high levels of DNA damage, P53 becomes activated and induces the apoptosis pathway.

DNA viruses

When DNA viruses infect cells, P53 becomes activated and induces the apoptosis pathway. All cells transformed by polyoma viruses or adenoviruses contain viral DNA integrated into one of their chromosomes. The integrated viral DNA expresses viral tumor antigens that inactivate the tumor suppressors Retinoblastoma and p53, stimulating the cells to enter S-phase even in the absence of normal physiogical signals that promote cell replication.DNA viruses have evolved mechanisms for inhibiting P53 induction of apoptosis:

  1. SV40, a large tumor antigen, binds the p53 DNA-binding domain to prevent it from bindings its control elements in DNA. This prevents p53 induction of apoptosis.
  2. Ad E1B 55K stimulates p53 DNA-binding, but contains a strong repression domain that turns p53 from a regulated activator into a constitutive repressor of p53-activated genes. This prevents p53 from inhibiting entry into S-phase and from inducing apoptosis.

Tumor suppression

Tumor tissues were analyzed via DNA sequencing, and the two p53 alleles were mutant in ∼50% of human metastatic cancers. Unlike other tumor suppressor genes, just one defective p53 allele is detrimental because it is a tetramer. Just one mutant p53 allele means that only 1/16 of all p53 tetramers will be function. Most common detrimental mutations involve p53 core domain that interacts with DNA. Germ-line mutation of p53 (Li-Fraumeni) leads to oncogenesis amongst almost all relatives, and of different tissues (breast/epithelial/etc).

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