P53
Historical
From 1979 to 1985
The Protéine p53 was discovered into 1979 in a simultaneous way by 4 research teams. Three of these teams were interested in the carcinogenic viruses and characterized a cellular Protéine of 53.000 Dalton able to interact with Protéine S expressed by these viruses (Team of L. Crawford, A. Levine and P. May). In parallel, the team of L. Old characterized a Protéine of the same molecular weight while seeking to identify new tumoral antigens. It is only into 1985 that one will be able to show that the protein highlighted by L. Old was the same one as that of the three other teams. The final name of p53 was given by L. Crawford in 1984. The Tp53 nomenclature proposed in 1998 is not yet fully used at the present time. In 1983 the team of A. Levine was the first to isolate the Gène p53 from mouse. The following year, several teams isolated the human Gène p53. What the scientific community was unaware of at that time it is that the whole of these Gène S isolated were transferred and had particular properties.
1985-1989
During these four years, the study of the properties of these transferred Gènes led the scientific community to classify the Gène p53 in the group of the Oncogène S.
1989-2007
It is into 1989 that two teams American (B. Voglestein and J. Mined) discovered that the Gène p53 was inactivated by changes in the human Cancers. At the same time, the team of A. Levine discovered that the Gène S p53 isolated were transferred. These observations and the possibility of studying a not transferred p53 made it possible to classify this Gène in the group of the genes suppressors of tumors. As from 1989, the number of laboratory working on p53 increased in a considerable way passing of ten to thousands with many clinical laboratories being interested in the changes of p53 in various human Cancers.
Summary of some striking facts:
-
Discovered mdm2, an inhibiter of p53
- Discovered apoptotic properties of p53
- Discovered answer p53 after genotoxic lesions
- Crystallization of the protein p53
- Discovered p63 and p73, Protein S connected with p53
the function of p53 in a normal cell
The function first of the Protéine p53 is to act as a Facteur of transcription. It functions while being fixed in a specific way on the regulating areas of Gène S of which it controls the expression. In a normal cell, in the absence of any stress, there is only very few p53 because this one is not necessary to the operation of the cell. This absence of p53 is caused by its partner mdm2 who, while fixing itself on p53, ensures his destruction. When the cell is in situation of stress, association between p53 and mdm2 is abolished what leads to an increase in the quantity of p53 in the cell. This first phase is named “phase of activation”. Many types of stress are able to activate the p53 like the lesions of DNA, the defects of division or cellular metabolism. In the second time, the p53 will undergo many traductionnelles modifications post which will make it possible to activate its function of factor of transcription. This phase is named “phase of modification”
In the third time (phase of answer), the p53 will activate the transcription of a great number of Gène S. the whole of this program will be able to lead to two results, either the stop of the cellular cycle or the Apoptose. The stop of the cellular cycle makes it possible the cell to stimulate its mechanisms of repair (of which some are directly activated by p53). When repair is carried out, the rate of p53 turns over to the normal and the cellular cycle begins again. In other case, the cell decides to commit suicide by a known mechanism biological under the name of apoptose what thus leads to the elimination of the damaged cell. This mechanism apoptotic is directly controlled by p53. At the present time, one does not know why and how certain cells choose a program apoptotic or a stop of the cellular cycle.
The Protéine p53 is thus a molecule essential to the maintenance of the integrity of the cell and its components. For this reason it is generally named “guardian of the genome”
If the p53 artificially is eliminated, the cell cannot answer the whole of the stresses any more and no stop of the cellular cycle or apoptose is observed.
Modification of the embarrassment p53 in cancers
Deteriorations of the gene p53 in human cancers
Nearly 50% of the human Cancers have a transferred p53 which lost its proliferative and anti anti capacities apoptotic. In cancers of the cervix (always associated with a Virus of the type HPV (papillomavirus), the situation is particular. A viral Protéine (E6 protein) is fixed specifically on p53 and destroys it what leads to the same situation as a Tumeur having a transferred p53.
Why the gene p53 is it frequently faded in human cancers
Obtaining an cancer cell requires an unstable environment which will make it possible the cell to acquire many changes of oncogenes or genes suppressor of tumor. The p53 being the most important agent of protection of the cell (see higher), that thus makes of it a privileged target of the mechanisms of canceration.
How the gene p53 is faded?
The studies of molecular epidemiology showed in a formal way that deteriorations of the gene p53 were due to the exposure to Carcinogènes in the cases of bronchial cancers (tobacco), cancer of the skin (rays UV) or cancer of the liver in the countries in the process of development (exposure to aflatoxine B1). In the others Cancers, their origins is more dubious.
Relation between loss of the function of p53 and the properties of the tumor
The goal of the cancerous anti therapy is to kill the malignant cells while harming the least possible the normal cells. The Apoptose is one of the ways which is induced by the radiotherapy or chemotherapy. Unfortunately, this program apoptotic is controlled by the p53. It is generally observed that the tumors expressing a faded p53 have less an good answer with the therapy compared to a tumor expressing a transferred p53. Nevertheless, there exist particular cases at which one observes the reverse. At present, the statute of the gene p53 is not used as marker in clinical routine.