p53

p53 is a tumor suppressor protein, also known as "Guardian of the Genome".  It  plays an important role in cell cycle control and apoptosis.  Defective p53 could allow abnormal cells to proliferate, resulting in cancer.  As many as 50% of all human tumors contain p53 mutants.

In normal cells, the p53 protein level is low.  DNA damage and other stress signals may trigger the increase of p53 proteins, which have three major functions: growth arrest, DNA repair and apoptosis (cell death).  The growth arrest stops the progression of cell cycle, preventing replication of damaged DNA.  During the growth arrest, p53 may activate the transcription of proteins involved in DNA repair.  Apoptosis is the "last resort" to avoid proliferation of cells containing abnormal DNA.

The cellular concentration of p53 must be tightly regulated.  While it can suppress tumors, high level of p53 may accelerate the aging process by excessive apoptosis. The major regulator of p53 is Mdm2, which can trigger the degradation of p53 by the ubiquitin system.

Target Genes

p53 is a transcriptional activator, regulating the expression of Mdm2 (for its own regulation) and the genes involved in growth arrest, DNA repair and apoptosis.  Some important examples are listed below.

1. Growth arrest: p21, Gadd45, and 14-3-3s.
2. DNA repair: p53R2.
3. Apoptosis: Bax, Apaf-1, PUMA and NoxA.

Regulation of p53

As mentioned above, p53 is mainly regulated by Mdm2.  The regulation mechanism is illustrated in the following figure.

Figure 4-H-5.  Regulation of p53. 
(a) Expression of Mdm2 is activated by p53. 
(b) Binding of p53 by Mdm2 can trigger the degradation of p53 via the ubiquitin system. 
(c) Phosphorylation of p53 at Ser15, Thr18 or Ser20 will disrupt its binding with Mdm2.  In normal cells, these three residues are not phosphorylated, and p53 is maintained at low level by Mdm2.   
(d) DNA damage may activate protein kinase (such as ATM, DNA-PK, or CHK2) to 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 while 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  After the DNA damage is repaired, the ATM kinase is no longer active.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.  

Roles of p53

The  roles of p53 in growth arrest and apoptosis are illustrated in Figure 4-H-6. p53 is also directly involved in DNA repair.  One of its transcriptional target gene, p53R2, encodes ribonucleotide reductase, which is important for both DNA replication and repair.  p53 also interacts directly with AP endonuclease and DNA polymerase which are involved in base excision repair.

Figure 4-H-6.  The  roles of p53 in growth arrest and apoptosis.  
(a) The cell cycle progression into the S phase requires the enzyme Cdk2, which can be inhibited by p21.  The progression into the M phase requires Cdc2 which can be inhibited by p21, GADD45 or 14-3-3s.  p53 regulates the expression of these inhibitory proteins to induce growth arrest.  
(b) Apoptosis can be induced by the binding of Caspase 9 to cytochrome c and Apaf1.  p53 may activate the expression of Apaf1 and Bax. The latter can then  stimulate the release of cytochrome c from mitochondria (see Mitochondria, Apoptosis and Aging). 

Review Articles:

p53–Mdm2—the affair that never ends - Carcinogenesis, 2002.

Cell cycle checkpoint signaling through the ATM and ATR kinases - Genes and Development, 2001.

p53 from complexity to simplicity: mutant p53 stabilization, gain-of-function, and dominant-negative effect - FASEB J., 2000.

p53 protein at the hub of cellular DNA damage response pathways through sequence-specific and non-sequence-specific DNA binding - Carcinogenesis, 2001.