p53 gene, also known as tumor protein 53 (TP53), encodes for a tumor suppressor protein which regulates the cell cycle and apoptosis. The p53 protein has been described as the guardian of the genome (1) because of its role in preventing genetic mutation. It belongs to a protein family which includes p53, p63 and p73 and these are structurally and functionally related to each other. However, p53 seems to have evolved as a tumor suppressor in higher organisms, while p63 and p73 play a role in normal developmental biology (2).
Structure of p53
P53 functions primarily as a transcription factor, and is biologically active as a homo-tetramer comprising of 4 X 393 amino acid residues. Each monomer ...view middle of the document...
It performs these functions by activating the transcription of various genes like p21 (growth arrest), p53R2 (DNA repair), Bax, Apaf-1 and PUMA (apoptosis) etc. The functions of p53 target genes are diverse, corresponding to the p53’s multifaceted regulatory activity (2).
Regulation of p53
Various stressors induce post-translational modifications and force p53 to be activated as a transcription regulator in these cells. This begins with phosphorylation of the N-terminal by protein kinases (like p38kinase, JNK1/2) at various serine residues, which allows binding of several transcriptional coactivators like p300 (3). These coactivators then acetylate the carboxyl terminus domain of p53, which exposes the DNA binding domain allowing it to induce a transcriptional activity.
Phosphorylation of p53 is a critical step as it also prevents its degradation by ubiquitination. In the absence of stress, p53 levels are maintained low through continuous degradation, by an auto-regulatory process. p53 activates the transcription of a protein MDM2, which is a E3 ubiquitin ligase. MDM2 covalently attaches ubiquitin to p53 and marks it for degradation by proteasomes(4). This is however reversible, by proteases like USP7 (5).
Therapeutic applications of p53 in Cancer
Therapeutic intervention to restore p53 function in tumors has been mainly focused on targeting destabilized oncogenic p53 mutant. Most mutations cause destabilization and unfolding of p53 structure. Hence, drug molecules are being designed to stabilize the protein at physiological temperatures and restore its transcriptional functionality (6).
Another approach is to target the negative modulators of p53 like MDM2. Many cancers with wild type p53 show increased expression of MDM2 which results in increased degradation and suppression of p53 function (6). Disruption of p53-MDM2 interaction by small molecules should result in restoration of p53 functionality in these cancers.
Role of p53 in other pathological processes
In contrast to the detrimental effects of loss in p53 function in cancer, activation of p53 by stress signals can also lead to several pathologies. For example, p53-mediated apoptosis can be related to the side effects associated with chemotherapies and radiation therapies (7). p53-mediated neuronal apoptosis also contributes to the pathologies seen in various neuro-degenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s diseases (8, 9, 10, 11).
Studies in diabetic mice indicate a p53-dependent senescence response in fat cells, which resulted in insulin resistance in obese mice (12). Also, inhibition of p53 function restores...