Secreted proteins are released from one cell to transmit a signal to another cell instructing a particular behavior such as cell growth, migration or survival. These proteins cannot act alone; they must act through a receptor or receptors on the receiving cell, so discovery of the receptor is also important.
Initially called MOB-5, this new protein has been renamed Interleukin 24 (IL-24), with the approval of the Human Genome Nomenclature Committee, because the investigators’ work demonstrates relationship to the family of proteins known as interleukins. These proteins are typically secreted by immune system cells in response to a triggering event, such as injury or infection. However, the Vanderbilt-Ingram team has found IL-24 and two receptors expressed in colon cancer cells, making it the first interleukin to be found along with its receptors in tumor cells.
"There is an old saying that cancer is like a wound that never heals," said Peng Liang, Ph.D., associate professor of Cancer Biology, whose laboratory did the work reported this month in the Journal of Biological Chemistry. "This gives credence to that old saying."
Using a process called differential display to compare gene expression between cancer and normal cells, the team found this gene to be expressed only in tumor cells and particularly those in which the oncogene (cancer-causing gene) RAS is activated. RAS is mutated frequently in colon and pancreas cancers, among others, and it appears from this group’s work that RAS activation leads to unregulated expression of IL-24 and its receptors.
"At the time, we didn’t know it was an interleukin, just that it was a secreted protein," Liang said. "Finding the difference between tumor and normal cells is really only the beginning of the story."
Once the team cloned the gene, however, its similarity to IL-10 and two other related interleukins, IL20 and IL22, was apparent, Liang said. Further research to test binding between IL-24 and the known receptors in the IL-10 family found that IL-24 binds to two different two-part (heterodimeric) receptors, and that it shares a subunit of these receptors with IL-20 and IL-22.
"If they share both sequence homology and receptor subunits, it provides strong molecular evidence that these interleukins are related," Liang said. "As a result, MOB-5 was properly renamed as a new interleukin."
The scientists also demonstrated that IL-24 can promote cell growth or prevent cell death. This was done using hemopoietic mouse cells that must have interleukin-3 (IL-3) to grow and survive. When the cells were made to express IL-24 receptors, in the absence of both Il-3 and IL-24, the cells died. In the absence of IL-3 but the presence of IL-24, the cells continued to live and grow.
Finding that IL-24 can support cell survival, and finding both IL-24 and its receptors in tumor cells, has an important implication, Liang said. This creates what is called an autocinre loop, through which a cell secretes a protein that then binds to a receptor on itself, sending its own signal to its nucleus. "The cell could then fuel its own growth and survival without the checks and balances by the neighboring cells," Liang said.
The next step will be to try to develop molecules to interrupt this autocrine loop, either by intercepting the IL-24 protein outside the cell after it is secreted, or by blocking the receptors so that the protein cannot bind and therefore transmit its signal back into the cell.
The team’s most recent work was published in the March 1 issue of the Journal of Biological Chemistry. It was supported in part by the National Institutes of Health. Vanderbilt co-authors include graduate student Mai Wang, and postdoctoral fellows Zhongjia Tan and Rong Zhang of the Department of Cancer Biology.
Journal
Journal of Biological Chemistry