p53 Structure
•p53 is mainly a sequence-specific transcription regulatory protein that binds to DNA as a tetramer.
•p53 can be divided into at least five functional domains involved in transcriptional activation, sequence-specific DNA binding, non-specific DNA binding, oligomerization, and binding by the MDM2 protein are indicated.
•Boxes I-V indicate distinct regions of p53 that are highly conserved between p53 proteins of diverse species.
Regulation of p53 Function
•p53 protein has a short half life (5-20 min). The amount p53 protein in cells is determined mainly by the rate at which it is degraded, rather than the rate at which it is made.
•p53 degradation proceeds through ubiquitinmediated proteolysis. The MDM2 acts as a p53specific E3 ubiquitin ligase and labels p53 with ubiquitin. MDM2 also enforces p53 transport into the cytoplasm where it is degraded by proteosomes.
•ARF stabilizes p53 by interfering with all of the know functions of Mdm2.
•MdM2gene is activated by p53. This negative feedback mechanism ensures that p53 is not over-activated.
Pathways Leading to p53 Activation
Three principal pathways lead to p53 activation:
-Ionizing radiation induces DNA breaks that activate ATM and Chk2, which phosphorylate N-terminal serine residues. This affects p53 interaction with MDM2 and subsequent degradation. .
-UV radiation and other types of stress activate the kinases ATR (ataxia telangiectasia related), leading to phosphorylation of N-terminal serine residues of p53.
-Oncogenes Ras or Myc may activate p19ARF. This inactivates Mdm2 and thus activates p53.
Consequences of p53 activation
•p53 may trigger growth arrest and apoptosis (cell death), depending in part on the stage of cell cycle and availability of survival factors.
•Activation of p53 in G1 blocks progression through the cell cycle, allowing damaged DNA to be repaired.
•p53 activation usually triggers apoptosis if a cell is committed to division.
Mutations of p53 in Human Cancer
Mechanisms of p53 Inactivation in Human Cancers
