p53 - Tumor Suppressor Gene and Cancers

Résumé du document

The tumor suppressor genes or antioncogene, is a gene that controls the cell cycle and regulates the proliferation capacity. Their protein product inhibits mitosis. By contrast, the maturation or the loss of the function of an antioncogene promotes the appearance and proliferation of tumors or cancer. An example of tumor suppressor gene (TSG) is p53. The product of the gene p53 is a protein of 53 kilodaltons (hence the name). p53, known also as TP53 (tumor protein) is a transcription factor discovered in 1979 and mapped to the short arm oh the chromosome 17 (NCBI 2007). Existing at a very low concentration in non-stressed cells, the p53 protein prevents a cell from completing the cell cycle. Under stress conditions, the p53 protein accumulates in the cell, binds in its tetrameric form to p53-response elements and induces the transcription of various genes that are involved in cell-cycle control, apoptosis, DNA repair, differentiation and senescence. The loss of p53 tumor suppressor gene activity by mutation or deletion of TP53 or inhibition of p53 allows the proliferation of the cells that are damaged under stress conditions. This uncontrolled proliferation can lead to tumor development. As such, p53 is described as "the guardian of the genome". Its activity and role in the cell is summarized in figure 1 (Chène P 2003).

Extraits

[...] miR-140, which induces p53 expression, is significantly elevated in colon cancer stem cells. This increases the proliferative rate and chemoresistance. So, miR-140 may be a candidate target to develop novel therapeutic strategy. Another marker of tumorigenesis is focal adhesion kinase a tyrosine kinase that is overexpressed in a variety of human tumors. It has been demonstrated that p53 can inhibit the FAK promoter activity. It also has been shown that FAK was overexpressed in tumors containing mutations of p53 compared to tumor with wild type p53 (Golubovskaya VM 2008). [...]

[...] An exemple of tumor suppressor gene (TSG) is p53. The product of the gene p53 is a protein of 53 kilodaltons (hence the name). p53, known also as TP53 (tumor protein) is a transcription factor discovered in 1979 and mapped to the short arm oh the chromosome 17 (NCBI 2007). Existing at a very low concentration in non-stressed cells, the p53 protein prevents a cell from completing the cell cycle. Under stress conditions, the p53 protein accumulates in the cell, binds in its tetrameric form to p53- response elements and induces the transcription of various genes that are involved in cell-cycle control, apoptosis, DNA repair, differentiation and senescence. [...]

[...] In the example of figure p53 mutation affects the expression of group 1 gees, and Ras mutation modifies the expression of group B genes. When both p53 and Ras are mutated in the same cell, they synergistically regulate a subset of genes know as cooperation response genes (CRGs), which turn out to be crucial meditors in tumor formation. Figure Example of oncegenic mutations in p53 promoting developemnt of cancers p53 and cancers Colorectal cancer Colorectal cancer is the third most frequent cancer in the world in both sexes and the third most frequent cause of cancer related deaths. [...]

[...] Figure p53 regulation in stressed cells Mutations and cancers Mutations are punctual events changing one base of the DNA of a gene. This modification changes the genetic information and the synthesized protein is modified. Mutations in p53 can modulate cell to proliferate indefinitely. This situation is then characterized by the development of a tumor. p53 never has an activity by itself and is often associated to other proteins as Ras. Ras is one of the protooncogene mutated in almost all human cancers. Non mutated, the H-Ras (human Ras) stimulate the cellular proliferation only when a signal is detected. [...]

[...] Like this, it would be possible to produce a therapeutic targeting of mutant p53 in putative cancer stem cells as well as the potential to enhance cytotoxic chemotherapy. Serum detection of p53 antibodies using ELISA has been recently developed. This phenomenon is inconstant (about one-third of the patients with a p53 gene mutation produce antibodies) and its mechanism is unclear. p53 antibodies are found in 25% of the patients with colorectal cancer. Bibliography Chène P. “Inhibiting the p53-MDM2 interaction: an important target for cancer therapy.” Nature Reviews Cancer 3 (2003): 102-109 Luo Elledge SJ. [...]