A Mechanism Behind Negative Tumor Suppressor Gene Function Identified

A Mechanism Behind Negative Tumor Suppressor Gene Function Identified
Main Category: Cancer / Oncology
Also Included In: Genetics
Article Date: 11 Jun 2010 - 1:00 PDT

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.

Source
The Cancer Institute of New Jersey

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A Mechanism Behind Negative Tumor Suppressor Gene Function Identified