The tumor suppressor gene p53, known as the “guardian of the genome,” is the most commonly mutated gene in human cancers. And even when the gene itself is not mutated, disruptions in the regulatory system that controls p53 may underlie most, if not all, cancers.
While p53 itself is a hot topic of study in cancer research, less is known about this cellular regulation system. Now a biochemist at the University of Texas Southwestern Medical Center hopes to untangle these pathways in an effort to restore p53’s normal function — a potential treatment for cancer.
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The tumor suppressor gene p53, known as the “guardian of the genome,” is the most commonly mutated gene in human cancers. And even when the gene itself is not mutated, disruptions in the regulatory system that controls p53 may underlie most, if not all, cancers.
While p53 itself is a hot topic of study in cancer research, less is known about this cellular regulation system. Now a biochemist at the University of Texas Southwestern Medical Center hopes to untangle these pathways in an effort to restore p53’s normal function — a potential treatment for cancer.
Glen Liszczak was recruited from Princeton University, where he was an associate research scholar, with the help of a First-Time Tenure-Track Award from CPRIT in 2018.
When it’s functioning normally, p53 helps prevent the accumulation of potentially problematic genetic mutations. When a defect is detected, p53 sends a signal to the cell to shut down, wait, and fix the problem before dividing and making more cells, Liszczak says. “It’s always around, but not always active, and it’s sitting there poised to jump into action.”
When the p53 protein is mutated, the genome becomes highly susceptible to DNA mutations. In the absence of functional p53, these mutations accumulate and can eventually cause cancer. Similar problems can arise even if p53 is normal, but the mechanisms controlling it are not functioning correctly.
“If p53 isn’t where it needs to be or there is not enough of it, it can’t do its job,” Liszczak says. “These are qualities regulated not just by mutations in p53 but by other proteins in the cell. We’re interested in how those other proteins are regulating p53.” This impaired regulation can also lead to cancer or other diseases.
Liszczak is focusing specifically on what are called post-translational modifications to p53. These modifications to the protein help control where it is in the cell and how much of it is around. Some cancers degrade p53 so that there just isn’t enough of it around to function the way that it normally does. Liszczak hopes to discover other pathways that regulate p53 and identify ways to restore its proper quantity and localization within cells.
He’s also interested in another enzyme involved in repairing DNA, called PARP1. Functioning PARP1 protein is required for the continued survival of cancer cells in breast and ovarian cancers with a mutation in the BRCA gene, also involved in DNA repair. Notably, these cancers are sensitive to drugs that inhibit PARP1, which are already successful FDA-approved anti-cancer therapeutics.
Liszczak believes that PARP inhibitors could be used to treat cancers other than breast and ovarian cancers. “Potentially we’ve only scratched the surface with these PARP inhibitors,” he says. “We’re trying to uncover the rules, in order to figure out which other cancers might be sensitive to these drugs.”
He said that CPRIT support enabled him to purchase state-of-the-art equipment and hire highly qualified personnel. “And having this funding means that I can be in the lab,” he says. “I don’t have to spend my first year or two in my office trying to get more money. It’s exciting!”
Liszczak studied chemistry and biology as an undergraduate at Ramapo College of New Jersey, and received his Ph.D. in chemistry from the University of Pennsylvania. He began his postdoctoral fellowship at Princeton in 2013, and became an associate research scholar in 2017.
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