The p53 protein and its gene TP53 have been studied extensively with 1000s of scientific studies published annually since its mercurial rise to prominence as an oncogene during the 1990s. Doing an advanced search only specifying that p53 be somewhere in the title of the scientific paper pulled up almost 33,000 results on PubMed, where nearly all scientific papers are stored.
The moniker “Guardian of the Genome” doesn’t come without tons of scrutiny and eventually consensus from numerous scientists in thousands of labs around the world. It turns out that the presence of p53 in our cells acts in different ways either binding directly to damaged DNA initiating repair or as a warning signal which recognizes severely damaged DNA and signals the cell to kill itself, known as apoptosis.
Mutated DNA is the genesis of cancer cells and mutated non-functioning p53 is linked to over 50% of all cancers. Without functioning p53 present the mutated cells are able to proliferate as cancer cells and that is the origin of tumorigenesis.
If p53 is the guardian of the genome then its arch nemesis is MDM2. MDM2 acts upon p53 by attaching a ubiquitin molecule, which is the signaling for the destruction of the p53 protein ubiquitylation. MDM2 is a 56 kDa protein that shares a genetic relationship with p53, as well. p53 can act upon the cell's DNA initiating the transcription or creation of MDM2 making these 2 antagonists inextricably linked.
In fact, the life of the cell is dictated by regulatory pathways. Being healthy means homeostasis where the balance of the pathways allow for the perfect copy of each protein to be expressed. The numerous studies of p53 show that when the gene is deleted that tumors begin to appear. People who inherit only one functional copy of the p53 gene (TP53) will most likely develop tumors in early adulthood, a disorder known as Li-Fraumeni syndrome. Studying the pathway has shown that p53 becomes expressed and stabilized more when DNA is damaged inside the cell. The p53 protein is the sentinel in the cell that initiates the programmed cell death pathway otherwise called apoptosis.
The MDM2 protein has been shown to take out the guard at the post no longer allowing the cell to commit to apoptosis or in other cases, repair its damaged DNA. However, this is actually a good antagonist to have because overexpression of p53 in the cell creates unnecessary cell death with its own special name, p53-overactivation-dependent cell death, referred to as podoptosis. In a healthy cell the feedback mechanism between these dualistic partners allows for cells to grow, flourish, and replicate. The problem with cancer is that the balance has shifted to the expression of MDM2 and away from p53 or to a mutated non-functioning form.
This perversion of balance has led to many pharmaceutical companies developing inhibitors and monoclonal antibodies targeting MDM2 and MDM4. The hypothesis is that by knocking out MDM2's ability to bind p53 you have allowed the p53 proteins present in the cell to do their function. There are several clinical trials underway that show preliminary data suggesting this hypothesis to be true. Companies like Aileron Pharmaceuticals are experiencing success in this area and putting efforts to advance ALRN-6924 for fighting solid cancers.
Figure 6. Rationale for targeting p53 in cancers. (A) Frequency of alterations are shown with mutation (green), deletion (blue), amplification (red), and combination of alterations (gray) in p53, MDM2, and MDMX in cancers derived from cBioPortal (5) (http://www.cbioportal.org). Insert shows the mutual exclusivity observed between MDM2 expression and p53 deletion in sarcomas. (B) Schematic representation of inhibitors in clinical trials (yellow box) or in preclinical studies (blue box) targeting the p53–MDM2/X axis. Compounds are either small molecules (green circle) or peptide (blue circle). Front Oncol. 2016; 6: 7. Published online 2016 Jan 27.
Now the strategy seems to expand the research and development to include other members of the MDM family, specifically MDMX, otherwise known as MDM4. It has been shown that MDM4 acts on p53 much the same way as MDM2. Therefore, cancer cells that are notorious for evading our bodies’ defensives can continue proliferating even after MDM2 is knocked out with the assistance of MDM4. This means the most effective manner to manipulate this pathway appears to require the inhibition of MDM4, as well.
It is fascinating to be on the receiving end in this new pursuit to target MDMX, aka MDM4 as the Chief Business Officer of ProMab Biotechnologies. We have been in several licensing meetings at ProMab Biotechnologies (PMB) regarding Clone 2D10F4 monoclonal antibody against MDM4 (catalog # 20247) from several parties alongside significant uptick in sales and inquiries from our distributors.
Through these meetings it has been divulged that this is the best clone on the market after they have screened the market for all available monoclonal antibodies (mAbs). I want to make sure that anyone doing research in this area can eliminate the countless hours searching and screening through all the available clones on the market when PMB is the source.
PMB has long positioned itself as a leader in oncology research solutions producing 1000's of monoclonal antibodies that have furthered advances in medical discoveries. In this group are the successful clone 5A10A9 mAb against MDM2 (catalog # 30749) and clone 4A8 mAb against p53 (catalog # 20338).
No matter if your research is directly focused on the p53 pathway and its regulatory partners MDM2 and MDMX/MDM4 or targeting another regulatory pathway, it will be important to include these 3 proteins in your panel. If you are looking for research services to conduct pre-clinical studies then you should come to PMB for a consultation where we can provide the resources required to generate the necessary data to move your project forward.
Frontiers in Oncology https://www.frontiersin.org/journals/oncology#
Wikipedia: https://en.wikipedia.org/wiki/Mdm2, https://en.wikipedia.org/wiki/P53,
Caitlyn Simson -