University of Wisconsin-Madison Team Finds Key to Common Cancer Pathway– Novel Regulators of p53 Identified; Discovery Related to “Guardian of the Genome” Protein Could Unlock New Therapies

Scientists have long known that the protein p53, when mutated, is a critical factor in the onset of many different kinds of cancer. In its unmutated form, however, it is known to protect against cancer. These dueling qualities make the p53 protein and the gene that codes for it among the most studied in biology, yet the molecular mechanisms that govern its stability and function have yet to be fully understood. On March 18, 2019, in Nature Cell Biology, a team led by University of Wisconsin-Madison (UW-Madison) cancer researchers Richard A. Anderson PhD, Professor, Head of Phosohoinositide Signaling Laboratory, and Vincent Cryns, MD, Chief of the Division of Endocrinology, Diabetes & Metabolism at the University of Wisconsin School of Medicine and Public Health, reported the discovery of an unexpected regulator of the critical protein, opening the door to the development of drugs that could target it. The article is titled “A Nuclear Phosphoinositide Kinase Complex Regulates p53.” "p53, like Janus, has two faces," says Dr. Anderson, referencing the two-faced Roman god of gates and doorways. "The p53 gene is the most frequently mutated gene in cancers, and, when mutated, it switches its function from a tumor suppressor to an oncogene that drives the majority of cancers." Typically, explains Dr. Anderson of the UW School of Medicine and Public Health, the p53 protein serves as "the guardian of the genome," initiating the repair of DNA damaged by ultraviolet radiation, chemicals, or other means, and preventing tumor growth. When mutated, however, the protein goes rogue, becoming more stable and abundant than its unmutated counterpart, accumulating in the nucleus of the cell and causing cancer. The UW research team, which includes study lead authors and postdoctoral fellows Dr. Suyong Choi and Dr. Mo Chen, found a new mechanism that drives this stability.
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