Green tea compound helps ‘genome keeper’ and tumor suppressor p53

An antioxidant found in green tea can increase the levels of p53, a natural anti-cancer protein known as the “guardian of the genome” for its ability to repair DNA damage or destroy cancer cells. Posted today in Nature communications, a study of the direct interaction between p53 and the green tea compound, epigallocatechin gallate (EGCG), points to a new target for the discovery of anticancer drugs.

“The p53 and EGCG molecules are extremely interesting. Mutations in p53 are present in over 50% of human cancers, while EGCG is the main antioxidant in green tea, a drink popular around the world, ”said Chunyu Wang, corresponding author and professor. of biological sciences at the Rensselaer Polytechnic Institute. “We are now discovering that there is an unknown direct interaction between the two, which points to a new path for the development of anti-cancer drugs. Our work helps explain how EGCG is able to stimulate the anticancer activity of p53, opening the door to drug development with EGCG-like compounds. “

Wang, a member of the Rensselaer Center for Biotechnology and Interdisciplinary Studies, is an expert in the use of nuclear magnetic resonance spectroscopy to study the specific mechanisms of Alzheimer’s disease and cancer, including p53, which he described it as “arguably the most important protein in human cancer.”

P53 has several well-known anticancer functions, including stopping cell growth to allow DNA repair, activating DNA repair, and triggering programmed cell death – called apoptosis – if the cells DNA damage cannot be repaired. One end of the protein, known as the N-terminal domain, has a flexible shape and can therefore potentially perform multiple functions depending on its interaction with multiple molecules.

EGCG is a natural antioxidant, which means it helps repair the almost constant damage caused by the use of oxygen metabolism. Found abundantly in green tea, EGCG is also packaged as an herbal supplement.

Wang’s team found that the interaction between EGCG and p53 preserves the protein from degradation. Typically, after being produced in the body, p53 is rapidly degraded when the N-terminal domain interacts with a protein called MDM2. This steady cycle of production and degradation keeps p53 levels low and constant.

“EGCG and MDM2 bind in the same place on p53, the N-terminal domain, so EGCG competes with MDM2,” Wang said. “When EGCG binds to p53, the protein is not degraded by MDM2, so the level of p53 will increase with direct interaction with EGCG, and that means there is more p53 for anticancer function. It’s a very important interaction. “

“EGCG binds the inherently disordered N-terminal domain of p53 and disrupts the p53-MDM2 interaction” was published with multiple grant support from the National Institutes of Health. At Rensselaer, Wang was joined in the research by Lauren Gandy, Weihua Jin, Lufeng Yan, Xinyue Liu, and Yuanyuan Xiao. The first author Jing Zhao is a former member of Wang’s lab, now at the faculty of China Agricultural University in Beijing, China. Co-first author Alan Blaney is a medical doctor. student at Upstate Medical University. Researchers also contributed from SUNY Upstate Medical Center; the University of Massachusetts, Amherst; New York University; the State University of New York at Binghamton; NYU Shanghai; and Merck Research Laboratories.