TUMOUR SUPPRESSOR - p53

INTRODUCTION

p53 has a short history starting from 1979. Arnold Levine, David Lane, and Lloyd Old, working at Princeton University, Imperial Cancer Research Fund (UK), and Sloan-Kettering Memorial Hospital respectively were the scientists who identified this protein

p53, the “guardian of the genome,” is a sequence-specific transcription factor whose activity is regulated through tight control of p53 protein levels. This transcription factor is encoded by the gene called TP53.p53 implies that its mass is 53 kDa but its actual size is smaller than that and it is about 43.7 kDa. This is due to the high content of praline amino acid in the p53 protein.

Gene responsible for the production of p53 is located in the short arm of the chromosome 17.Activity of the p53 depends on its concentration therefore the concentration is kept under tight control. Normally, levels of p53 are kept low by its association with the mdm2 oncogene product, which binds p53 and keep it away from the nucleus for proteolytic degradation. If there is any stimuli which can damage DNA such as irradiation, p53 will be phosphorylated by several kinases. This will regulate the DNA damage check point. This causes dissociation of p53 from mdm2, leading to increased p53 protein levels. This activates transcription of genes leading to cell cycle arrest (p21^Cip1/Waf1) or apoptosis.

STRUCTURE

Human p53 has 393 amino acids and it consists of seven domains.

1. Activation domain1 activates transcription factors: residues 1 to 42.
2. Activation domain 2 has the apoptotic activity; residues 43 to 63.
3. Proline rich domain is also important for the apoptotic activity of the p53: residues 80 to 94.
4. DNA core binding domain (DBD) is the central portion of the protein and it contains one Zn atom and several arginine amino acids : residues 100 to 300
5. Signaling domain : residues 316 to 325
6. Oligomerisation domain : residues 307 to 355
7. C-terminal domain is involved in down regulation

FUNCTIONS OF p53

This transcription factor has many functions. The main objective of all those functions is to ensure the maintenance of physiologically normal cell cycle thereby prevention of the occurrence of malignancies. Main functions are;

1. Activation of DNA repair system
2. Recognition of DNA damage
3. Initiation of apoptosis

p53 AND DISESSES

p53 plays a significant role in occurrence of many genetic and acquired diseases. p53 is a transcription factor encoded by a gene whose disruption is associated with approximately 50 to 55 percent of human cancers.p53 can be damaged either by genetically or by environmental causes ( chemicals, irradiation or viruses).

Damage to the gene which encodes p53 can lead to development of many childhood tumours. Li-Fraumani syndrome is a condition which occurs due to the some derangement in the TP53 gene. Human Papiloma Virus is a known virus which can damage TP 53 gene therefore it can make the person more vulnerable for carcinoma of the cervix.

RECENT DEVELOPMENT

There are thousands of researchers going on to describe the value of p53 in cancer management. The present invention relates to a new method for the treatment of cancer. More particularly, it relates to a method of treating cancer by regulating the cellular levels of the p53 protein. It also relates to vectors for gene therapy which make it possible to regulate the p53 protein, as well as the pharmaceutical compositions containing them.