A Mechanism Behind Negative Tumor Suppressor Gene Function Identified

Scientists Identify a Mechanism that Promotes Negative Function in Tumor Suppressor Gene

Team Including Researchers from The Cancer Institute of New Jersey Tap in to p53 Regulation

Newswise — The p53 gene has been a well-documented player in the prevention of tumors. It is considered the most frequently mutated gene in human tumors with more than half harboring p53 mutations (Bennett et al., 1999). These mutations often can be caused by disruption in normal p53 function. A team of investigators from The Cancer Institute of New Jersey and the Institute for Advanced Study -- which includes a researcher who co-discovered p53 some 30 years ago -- has identified a mechanism that interrupts normal p53 function, thus causing negative impact which can lead to tumor development. CINJ is a Center of Excellence of UMDNJ-Robert Wood Johnson Medical School.

In recent years, it has been shown that p53 is affected by the micro-RNA (miRNA) molecule. The miRNA molecule plays a key role in how genes translate coded messages into protein or a genetic material known as RNA and how those messages are delivered for use in cells. It is a specific form of this molecule known as miR-504 that investigators explored in this latest research (Negative Regulation of Tumor Suppressor p53 by microRNA miR-504), which will be published in tomorrow’s print edition of Molecular Cell.

The team looked at experimental models with colon, lung and breast cell lines containing human p53. Levels of p53 protein are typically increased in cells when these cells are responding to various stressors including DNA damage. This increase leads to the decoding of select p53 target genes and enables various cell responses, such as interruption in the cell cycle and even cell death. What researchers found is that when too much miR-504 is present in this cell environment, it decreases p53 protein levels and related tumor suppressor functions in the cell, thus promoting tumor development in these experimental models.

CINJ member Zhaohui Feng, MD, PhD, assistant professor of radiation oncology at UMDNJ-Robert Wood Johnson Medical School, is the senior author of the study. “Much remains to be learned about this new class of regulatory molecule. But as scientists continue to elucidate its role, it is quite evident that microRNAs impact genetic regulatory function,” said Dr. Feng. “Since p53 plays a critical role in tumor suppression, our results further highlight the importance of microRNAs in the role of tumor development. By identifying specific microRNAs, such as miR-504, scientists may one day be able to manipulate which genetic functions can be switched on and off, thus helping to better preserve tumor suppression function in these genes.”

In addition to the Feng laboratory, the CINJ laboratories of lead author Wenwei Hu, PhD, CINJ member and assistant professor of pediatrics at UMDNJ-Robert Wood Johnson Medical School; and Arnold J. Levine, PhD, CINJ resident member, professor of pediatrics and biochemistry at UMDNJ-Robert Wood Johnson Medical School, and professor at the Institute for Advanced Study, worked collaboratively on this research. Both Drs. Feng and Hu previously served as postdoctoral researchers in the Levine laboratory, which has a concentrated focus on p53 and genetic study. Dr. Levine is credited with co-discovering p53.

Other authors on the study are: Chang S. Chan, The Institute for Advanced Study; Rui Wu, CINJ and UMDNJ-Robert Wood Johnson Medical School; Cen Zhang, CINJ and UMDNJ-Robert Wood Johnson Medical School; Yvonne Sun, CINJ and UMDNJ-Robert Wood Johnson Medical School; Jun S. Song, Institute for Human Genetics at the University of California, who was at the Institute for Advanced Study when the research was conducted; and Laura H. Tang, Memorial Sloan-Kettering Cancer Center.

The team notes further studies to investigate the biological significance of miRNA’s negative regulation of p53 in tumors are being carried out.

The work was supported by grants from the National Institutes of Health (1R01CA143204-01, Feng) and the New Jersey Commission on Cancer Research (Feng). Dr. Zhang was supported by a New Jersey Commission on Cancer Research postdoctoral fellowship.

About The Cancer Institute of New JerseyThe Cancer Institute of New Jersey (www.cinj.org) is the state’s first and only National Cancer Institute-designated Comprehensive Cancer Center dedicated to improving the detection, treatment and care of patients with cancer, and serving as an education resource for cancer prevention. CINJ’s physician-scientists engage in translational research, transforming their laboratory discoveries into clinical practice, quite literally bringing research to life. To make a tax-deductible gift to support CINJ, call 732-235-8614 or visit www.cinjfoundation.org. CINJ is a Center of Excellence of UMDNJ-Robert Wood Johnson Medical School.

The CINJ Network is comprised of hospitals throughout the state and provides a mechanism to rapidly disseminate important discoveries into the community. Flagship Hospital: Robert Wood Johnson University Hospital. Major Clinical Research Affiliate Hospitals: Carol G. Simon Cancer Center at Morristown Memorial Hospital, Carol G. Simon Cancer Center at Overlook Hospital, Cooper University Hospital and Jersey Shore University Medical Center. Affiliate Hospitals: Bayshore Community Hospital, CentraState Healthcare System, JFK Medical Center, Mountainside Hospital, Raritan Bay Medical Center, Robert Wood Johnson University Hospital at Hamilton (CINJ at Hamilton), Saint Peter’s University Hospital, Somerset Medical Center, Southern Ocean County Hospital, The University Hospital/UMDNJ-New Jersey Medical School*, and University Medical Center at Princeton. *Academic Affiliate