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September 7, 2007

Study Reveals New Details Of Tumor Suppressor Gene P3 Regulation

Topics: Medicine
A study conducted by scientists at The Wistar Institute reveals new levels of subtlety in the body's management of this all-important tumor suppressor gene and the protein it produces.
p53%20two.jpgThe p53 gene was first known in its aberrant role as an oncogene, or tumor promoter, and is found in mutated form in over half of all cancers. A newly formed p53 protein is unstable and present in low levels under normal conditions. However, when the cell is confronted by stress, such as ultraviolet damage, ionizing radiation or oncogene activation, p53 is stabilized by the addition of certain chemical groups and increases in concentration. Due to its essential role as a tumor suppressor, p53 can be thought of as continuously monitoring the integrity of the DNA molecule, and when defects are found to take steps to either correct the errors or destroy the cell.
When changes in the DNA are detected, p53 protein binds to a gene to promote the transcription of another protein, p21. This protein, in turn, enters the metabolic process of the cell to shut down the cell cycle at the G1 or growth phase. 4 This would allow time to repair the DNA just before it enters the DNA replication phase. If this repair were possible, it would reduce the possibility of mutations and progression towards cancer. If repair is not possible, p53 stimulates the cell to enter a pathway leading to apoptosis, or programmed cell death. In total, p53 targets around 150 genes to prevent proliferation of damaged cells.
However, p53 can also function as an oncogene. It appears to be very subject to mutation.
Most mutations occur in the DNA-binding region of the gene. The resultant protein has an abnormal structure and cannot function. With the DNA structure now unprotected against defects, mutations can accumulate, checks and balances on the cell cycle can fail to operate, and cell growth can proceed unchecked.
As is pointed out in an article yesterday at Science Daily on the results of the study at Wistar Institute, so vital is the p53 tumor suppressor gene in controlling cancer that its dysfunction is linked to more than half of human cancers. At the same time, the gene's capacity for shutting down cell growth, even causing cells to commit suicide if necessary, is so absolute that it must be tightly regulated to maintain the optimal balance between protecting against cancer and permitting normal growth.
... experiments show that, while the addition of a specific molecule at a particular site on the p53 protein prevents it from acting, the addition of a second copy of the same molecule at the same site reverses the effect, sending p53 into action. Further, removal of the second copy returns the protein to its repressed state.

In addition to the implications for understanding the activity of the p53 gene, the findings also outline an important new cycle of gene-regulating modifications involving the addition and removal of the molecules, called methyl groups, that may be widespread in the genome. A report on the study appears in the September 6 issue of Nature.

"The p53 tumor suppressor is extremely potent in halting cell growth," says Shelley L. Berger, Ph.D., the Hilary Koprowski Professor at The Wistar Institute and senior author on the study. "So, as critical as p53 is in protecting against the unchecked growth of cancer, you don't want it constantly on. If it were always on, your cells wouldn't be able to grow normally. Yet it needs to be constantly on call for activation against cancer and other aberrant cellular developments. Our study shows one way that the cell, working at one particular location on the p53 protein, maintains a nuanced but firm control over the gene's activity."

Responsible for tumor suppression throughout the body, the p53 gene is mutated or otherwise disabled in a majority of human cancers. When working properly, the protein produced by the p53 gene acts by binding to DNA to activate other genes that direct cells with damaged DNA to cease dividing until the damage can be repaired. Cells with such damage include cancer cells, since all cancers track to genetic flaws of one kind or another, whether inherited or acquired. If repairs cannot be made, p53 commands the cells with damaged DNA to self-destruct so they are no longer a danger to the body.

This powerful ability of p53 to shut down cell division and induce cell death points to why fine-tuned regulatory mechanisms such as the one outlined in the new study are crucial for cellular survival.

Of interest to cancer patients not only that significant progress is being made in understanding how p53 regulation occurs and how it might possibly be manipulated, but also Treatment approaches based on restoring p53 function are already being studied, and that scientists are already considering novel approaches such as combining tumor suppressor gene therapy and chemotherapy in the treatment of neoplasms. Although there's still a ways to go before medical science completely understands p53 function and regulation to the point of being able to use it as a reliable treatment modality, but rest assured that scientists are indeed getting close.

Cross posted from New Hope Blog

Posted by Richard at September 7, 2007 6:00 PM

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