Master Tumor-Suppressor Gene Helped by Junk RNA

Three micro-RNA genes appear to be major collaborators of protective gene p53, and their loss is tied to a common type of lung cancer.

Scientists have demonstrated in thousands of studies that the p53 gene deserves its reputation as "the guardian of the genome.” It initiates a host of other genes in the setting of varied cell stresses, permitting repair of damaged DNA or promoting cell death when the cell damage is too great. A major net effect of p53's action is to prevent development of cancerous cells.

Now, University of Michigan (U-M) Medical School (Ann Arbor, USA) scientists have provided the most comprehensive evidence yet that p53 also regulates a trio of genes from the realm of so-called "junk” genes--about 97% of a cell's genetic material whose function is only beginning to be understood.

The study revealed, "in the ‘junk' lies treasure, in terms of critical knowledge about how normal cells stifle cancer or succumb to it,” remarked Guido Bommer, M.D., the lead author of findings, which were published in the August 7, 2007, issue of the journal Current Biology.

"The findings in the study offer new insights into specific mechanisms by which the expression of hundreds to thousands of genes and proteins is altered in the roughly 50% of cancers that carry mutations in the p53 tumor-suppressor gene,” stated Eric Fearon, M.D., Ph.D., senior author of the study and deputy director of the U-M Comprehensive Cancer Center. Scientists continue to search for details of what goes wrong when p53 is defective and cannot perform its tumor-fighting functions.

The U-M study is one of four recent studies from laboratories worldwide showing that p53 typically gets support from members of a small family of micro-RNA genes. The studies are part of a larger effort to understand the function of micro-RNA (also know as miRNA).

Scientists have long known the importance of messenger RNA (mRNA), which carries protein-making instructions. However, until recently, little was known about micro-RNA genes. It is now well recognized that miRNAs regulate the levels of mRNAs, and/or the levels of the proteins produced from mRNAs.

The U-M research team studied the roles of the three genes that make up the miRNA34 family. They showed that the miRNA34 genes work together with p53, then went on to find which other genes the family regulates. They discovered that the miRNA34 genes showed distinct effects on other genes that control the timing of cell proliferation and division. They also found that the miRNA34 gene family regulated the levels of the Bcl-2 protein, a key factor that enhances a cell's resistance to death-inducing stimuli.

The investigators went on to determine if expression of the miRNA34 genes was compromised in human lung cancer cells. "We found that expression of two of the miRNA34 genes was lost in almost two-thirds of lung adenocarcinomas,” said Dr. Bommer.

Adenocarcinomas represent the most common type of non-small cell lung cancer, which is the most frequently diagnosed type of lung cancer. When expression of the miRNA34 genes was restored in lung cancer cells, some of the aberrant growth properties were inhibited.

The discoveries of the role of micro-RNAs in tumor suppression could have implications for future cancer therapies. However, It is important to note that micro RNAs alone are not likely to offer new cancer treatment or prevention agents, according to Dr. Fearon, who is a professor of oncology, internal medicine, pathology, and human genetics at the U-M Medical School.

"However, because of the small size of mature miRNAs, there is optimism that it may be possible to deliver modified nucleic acids that might mimic the effect of the miRNAs,” Dr. Fearon noted. If engineered nucleic acids were to prove successful in more laboratory studies, he added, they might be pursued further in clinical trials as anti-cancer agents, either alone or more likely in combination with other anti-cancer agents.


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