The Story of MDM2
An understudied but important gene that serves as the ‘gatekeeper’ of the ‘guardian of the genome.’
Oncologist David Lane first named the TP53 gene the ‘guardian of the genome’ in 1992. Shortly after, scientists initiated a whirlwind of studies to understand it better. Their early work demonstrated that the protein that TP53 makes – called p53 – suppresses tumors in tissue cultures and in animals. Scientists then found that it carefully watches over sick and damaged cells by activating molecular reinforcements to repair them, or by goading sick cells toward destruction before they inflict even more bodily damage.
Since TP53’s discovery in 1979, it has become the most widely studied gene of its class, with nearly 60,000 scientific papers published on it following its debut.
But discussions of TP53 wouldn’t be complete without another gene called MDM2 – or Mouse Double Minute 2 Homolog. If TP53 is the ‘guardian of the genome,’ then MDM2 is the ‘gatekeeper of the guardian.’ Its job is to regulate levels of p53 within the body.
While MDM2 has not been as vigorously studied as TP53, the gene plays crucial roles in the body. The protein it makes, called Mdm2, not only balances levels of p53, but is involved in other essential cellular pathways and processes as well.
MDM2 and Cancer
The MDM2 gene was first discovered in 1992 when researchers found that it was responsible for turning a line of healthy rodent cells into cancerous cells. Subsequent studies found that if the MDM2 gene was artificially manipulated to produce more of its protein in strains of mice with diminished immune systems, the mice became more likely to develop tumors in their connective tissues. This included their lymphatic systems, muscles, bones, and the linings of their blood vessels.
This classified MDM2 as an “oncogene.” Over time, oncogenes can eventually cause cancer by becoming altered, or mutated, in a way that causes them to make malformed proteins that grow in abundance in cells. Because tumors lack the regulatory switch to turn this protein production “off,” tumors generally contain higher-than-normal levels of mutated oncogenes and the proteins they make.
While MDM2 plays many important roles in the cell, such as in the synthesis and repair of DNA, it is perhaps most widely known for its role in cancer. Copies of the mutated oncogene are present in more than a third of 47 sarcomas – or cancers of connective or non-epithelial tissues – such as muscle, fat, bone, and organ tissues, as well as tissues that line the joints and blood vessels. MDM2 is often correlated with a poor prognosis in certain human cancers, including those of the breast, lung, stomach, esophagus, colon, and prostate.
And while about 50 percent of cancers contain a damaged form of TP53, 20 percent of tumors contain many copies of the MDM2 gene. The Mdm2 protein’s oncogenic – or cancer-causing capacity – stems from its ability to bind to the p53 protein, which subsequently blocks p53 from snuffing out tumors.
Here’s how: Mdm2 and p53 proteins have an unusual partnership in the cell. They maintain levels of each other through a negative feedback loop: high levels of the Mdm2 protein cause a degradation of p53; thus when Mdm2 levels are high, p53 levels are low. This auto regulatory loop ensures that p53 is kept at bay in healthy cells, because its tumor suppressing repair functions are not needed.
But if the MDM2 gene is mutated – or damaged due to gene copying mistakes or chemical or environmental exposures – it can get stuck in the “on” position, leading to a never-ending flood of Mdm2 protein. This, in turn, blocks the tumor suppressing functions of the p53 protein. When tumors aren’t suppressed, they can replicate out of control and can eventually lead to cancer.
A Therapeutic Target
While the Mdm2-p53 protein interaction is highly complex, a large field of synthetic chemists and pharmacologists devote their time to devising strategies that home in on therapies that focus on this interplay. Since many common cancers arise from a damaged or inhibited p53 protein, many treatments focus on delivering more p53 to cells that need it.
A treatment for head and neck cancer, which uses a virus to deliver p53 to cells, was approved in China in 2004. Other techniques involve restoring the function of p53 in the cell by administering a vaccine that contains a small molecule, called ellipticine, which attacks p53’s mutated form.
Alternatively, if you could intercept the activation of MDM2, you could boost levels of p53 when you need it most. One “gene silencing” technique involves blocking the cellular machinery that makes Mdm2 proteins at the gene level, thereby freeing up the production of tumor-quashing p53 proteins. One promising strategy uses small strings of DNA or RNA molecules or enzymes that attach to the MDM2 gene and prevent it from being “turned on.”
But while these techniques show promise in cell culture and mouse studies, they have yet to be tested in humans in preclinical or clinical development. Several groups in China have successfully used nanoparticles and lipid structures to deliver synthetic RNA molecules into tumors, which could potentially be turned into a cancer treatment down the road.
Another strategy targets the spot where the Mdm2 and p53 proteins link together. By developing small molecules that bind to pockets of the Mdm2 protein, they can effectively block Mdm2 from attaching to p53, thus freeing up p53 to spread throughout the cell. Other compounds, such as those derived from ginseng, turmeric, and some fruits and vegetables also seem to decrease the expression of the Mdm2 protein in tumors.
Looking Toward the Future
More research is needed to further clarify the roles of the p53-Mdm2 interaction and to understand the circumstances under which this protein partnership can be successfully targeted for therapeutics. The good news, however, is that there is a huge effort underway to improve cancer treatments by generating novel strategies that zero in on the complex interaction between the ‘guardians’ and ‘gatekeepers of the genome.’
The molecular process, while complicated, is likely to offer viable approaches as many laboratory and clinical tests are ongoing. Make sure that you discuss all possible treatment options with your doctor, depending upon the nature of your mutation.