P53 and Mdm2 interaction: How p53 concentration is maintained at low level in normal cells?

In normal cells, the concentration of p53 is maintained low by a regulator protein called Mdm2, which can trigger the degradation of p53 by the ubiquitin system. In normal cells, the p53 level should be maintained low as high level of p53 may accelerate the aging process by excessive apoptosis.

How p53 concentration is regulated by Mdm2?
The regulation mechanism is illustrated in the following figure.
Regulation of p53 Mdm2 interaction
(a) Expression of Mdm2 is activated by p53
(b) Binding of p53 by Mdm2 can trigger the degradation of p53 via the ubiquitin system.

Summary flow chart
P53-Mdm2 complex---> degradation of p53 by ubiquitination
(c) Phosphorylation of p53 will disrupt its binding with Mdm2.  In normal cells, as p53 is not phosphorylated, Mdm2 mediated degradation will not occur.  
Summary flow chart
Phosphorylated P53-Mdm2 complex---> no degradation of p53 by ubiquitination
(d) DNA damage may activate protein kinase (such as ATM, DNA-PK, or CHK2) which phosphorylate p53 at one of these three residues, thereby increasing p53 level.  Since Mdm2 expression is activated by p53, the increase of p53 also increases Mdm2, but they have no effect as p53 is phosphorylated. 
After the DNA damage is repaired, the ATM kinase is no longer active.  p53 will be quickly dephosphorylated and destroyed by the accumulated Mdm2. 

Summary flow chart
DNA damage—> activates Kinases-->Phosphorylation of p53 by kinases-->Phosphorylated P53-Mdm2 complex--> no degradation of p53 by ubiquitination
After DNA repair -->Dephosphorylation of p53-->High levels of already formed Mdm2 -->Mdm2 mediated degradation of p53 by ubiquitination
  • p53 : The Most Frequently Altered Gene in Human Cancers. Nature Education 3(9):6
  • Momand, J., Zambetti, G. P., et al. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69,1237–1245 (1992).
  • Haupt, Y., Maya, R., et al. Mdm2 promotes the rapid degradation of p53. Nature 387, 296–299 (1997).

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