Boston-Scientists at Beth Israel Deaconess Medical Center (BIDMC) have discovered a gene that regulates the oncogenic gene MDM2. MDM2 in turn regulates the tumor suppressor protein p53. But this group of scientists found that these genes are not "on-off" switches of the MDM2 gene, but more like a dimmer switch, which suggests a more complex signal transmission path, which is sensitive to changing environments.

The new discovery of upstream genes reported in the "Cancer Cell" magazine published on August 17 involved p53 cell signaling pathways, which may point to new drug targets that help kill tumors. The discovery also points to possible cancer risk biomarkers, which may one day help patients take preventive measures against cancer.
p53 prevents tumors from appearing in the body, and it has problems in 50% of cancers. p53 is called the guardian of the genome. It is part of a complete defense system composed of various proteins. It allows cells to repair DNA damage caused by daily environmental attacks by pausing the normal cell division cycle, thus preventing cancer from appearing. If the damage is too severe to repair, p53 will trigger cell death.

Wenyi Wei, an assistant professor of pathology at the Beth Israel Deaconess Medical Center and Harvard Medical School, said that because p53 is destructive, it exists in a "yin and yang" way-like balancing it with the opposite. "When the DNA is damaged, MDM2 retreats, allowing p53 to suspend the cell and repair it," Wei explained. "And when MDM2 reappears, p53 disappears and the cell cycle returns to normal." However, it is known that MDM2 is also an oncogene, because too much MDM2 will completely stop p53, thus weakening its ability to prevent cancer.

In this new study, Wei and his collaborators found that MDM2 does not simply disappear gradually, but is actively degraded by the combined action of a pair of enzymes. One of these enzymes is called casein kinase I (CKI), which is activated when cells detect DNA damage, although the details of this activation are not yet clear. Its job is to phosphorylate MDM2, which causes MDM2 to be destroyed by another enzyme, beta-TRCP1. beta-TRCP1 works by labeling MDM2 with a small protein called ubiquitin, which is like labeling a piece of unwanted furniture with “garbage”. The 26S proteasome then cleaned up MDM2 like a garbage collector, releasing the DNA repair work of p53.

Interestingly, Wei found that CKI applying a phosphorylation marker to MDM2 is not enough to ensure that beta-TRCP1 destroys this protein. "It's more of a dimmer switch than an on-off switch," Wei said. The research team found 17 to 23 phosphorylation sites-that is, the location of the "junk" label on this protein. "It looks like the cells want to be able to adapt to the environment," Wei said. "Not completely yes or no, you give a gradual 'yes', then a complete 'yes', the protein is marked as needing to be destroyed."

"This new study defines how MDM2 is regulated by protein degradation after DNA damage. Although it has long been known that p53 is activated, the mechanism by which this occurs is far less clear," said William Hahn, associate professor at Harvard Medical School . "These types of experiments may eventually achieve treatment methods to intervene in this mechanism."

Since more than half of tumors have too little p53, an existing treatment strategy under development involves suppressing the MDM2 of tumor cells, and then allowing p53 to perform its repair work or destroy irreparable cells.

A new treatment possibility is to go further upstream of this signaling pathway to promote CKI. Wei speculates that increasing the concentration of CKI may reduce MDM2 and release p53. However, Wei said: "It is easier to make an antagonist to inhibit a protein than to make an agonist to promote a protein."

Another possibility is that clinical researchers may wish to study clinical tumor samples to find out whether CKI or beta-TRCP1 are mutated in different types of cancer. If so, these mutations may become biomarkers of cancer risk. Therefore, they may encourage patients to take preventive measures, similar to the BRCA1 gene involved in breast cancer risk may affect the way patients with extremely high cancer risk take preventive surgery.

Wei's research has so far focused on cell culture and mouse research. His research will continue to take more measures to understand how DNA damage induces the p53 repair pathway. His research, combined with recent findings by Galit Lahav, a co-author of the Department of Systems Biology at Harvard Medical School, also showed that cells exhibit regular p53 fluctuation pulses during DNA repair, and Wei hopes to better understand it. "This is not a high or low p53 concentration. The cell dynamics are always changing," Wei said.

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