Researchers in the UNC Gillings School of Global Public Health have identified the mechanism by which p53 – an important cellular protein, also known as the tumor suppressor and regulator of cellular metabolism – functions in the cell. This newly discovered mechanism could potentially be targeted for the development of future cancer therapies.
[Photo: Dr. Natalia Krupenko]
The discovery is part of ongoing research in the lab of Dr. Natalia Krupenko, assistant professor of nutrition at the Gillings School and the UNC Nutrition Research Institute. Dr. Krupenko also is lead author of a new publication on the finding, titled “CerS6 is a Novel Transcriptional Target of p53 Activated by Non-Genotoxic Stress,” published online June 16 by The Journal of Biological Chemistry.
In the paper, Dr. Krupenko and colleagues outline their investigation into how the p53 protein increases expression of a specific gene of the sphingolipid class, which in most body tissues is not very active.
Under stress conditions, however, mammalian cells activate the p53 protein in order to either adapt to changing conditions or eliminate severely compromised cells. The researchers found that during this process, many genes are regulated by p53 – in other words, it ‘turns genes on or off’ – but only a few genes come into direct physical contact with the protein.
In related research, Dr. Krupenko’s lab recently found that disruption in the body’s supply of an essential nutrient – B9 vitamin folate – results in a specific cellular response involving p53. The new publication reveals exactly how the p53 protein activates affected cells to initiate a program for minimizing and eliminating related damage.
Applying overlapping molecular biology approaches, the investigators were able to identify the unique place in the sphingolipid gene where the p53 protein binds and activates the gene, thus establishing it as a direct target.
Knowing about this link, through which p53 recognizes specific needs in the body and tells cells how to respond, may be highly useful in developing novel drugs for cancer therapy.
Co-authors from UNC include first author Dr. Baharan Fekry, former postdoctoral fellow, Dr. Kristen Jeffries, current postdoctoral fellow, and Dr. Amin Esmaeilniakooshkghazi, former postdoctoral fellow, all with the Nutrition Research Institute, as well as Dr. Sergey Krupenko, professor of nutrition at the Gillings School and researcher at the Nutrition Research Institute.