Many proteins have been found in cancer research that are associated with either errant cell division or with uncontrolled growth, but ARF is the first "master molecule" that seems to be involved in both crucial aspects of the cell cycle, say the researchers, who published their discovery in the November issue of the journal, Molecular Cell.
The work helps explain why so many human cancers -- more than 40 percent -- are found to have altered ARF proteins, says the study's lead author, Yanping Zhang, Ph.D., assistant professor in the Department of Molecular and Cellular Oncology.
The picture of molecular cell processes now painted by the investigators also suggests that drugs might be developed that could mimic normal ARF function, he says.
"In cancer, cells need to grow first, and then divide, and we have found the first protein that can, in a coordinated fashion, put the brakes on both of these steps," says Zhang. "This protein, or those associated with it, might offer some new therapeutic strategies to investigate."
ARF and the proteins it has power over are major players in cancer development, say the investigators. ARF is the second most frequently altered protein in cancer development, and it helps manage the tumor suppressor protein p53, which is the most common protein defect associated with cancer. That was already known. Now, this study shows that ARF also controls a protein known as B23, which is found in abnormally high levels in almost every tumor cell -- but, before this work, no one knew both proteins interacted.
In order for a cell to grow, it must produce new proteins. To do that, small round bodies within the cell known as ribosomes develop, based on instructions from the cell's DNA genetic code, which then guide production of proteins. Putting together ribosome "protein factories" from RNA (decoded DNA) and other molecules is one of the major activities of a cell; without ribosomes, protein production would shut down.
Ribosomes are made up of RNA (decoded DNA) and proteins, and Zhang and colleagues found that ARF can help limit the production of ribosomes, and hinder growth. It does this by "degrading" or inhibiting the B23 protein, which helps trigger mature formation of the ribosome factory. Without B23, ribosomes cannot form, proteins aren't produced, and a cell cannot grow, says Zhang. Normal cells do need some amount of B23, but cells that are constantly growing, as cancer cells do, contain high levels of B23, he says.
At this point, researchers do not know whether high levels of B23 imply that ARF proteins are mutated, unable to limit production of ribosomes, or if there is just too little ARF protein to degrade high levels of B23 protein.
"B23 has been found to be highly over-expressed in many tumors, such as in breast and ovarian cancers, but no one knows why that is or how to control it," says Zhang. "Now we at least know that ARF can control B23, and it may mean a drug that mimics ARF could help inhibit the protein and help control cell growth."
Cells that grow often divide, and ARF has a known function in regulating that aspect of the cell cycle, says Zhang. ARF works in conjunction with the p53 protein, a tumor suppressor that blocks the cell cycle if the cell starts to grow erratically. Abnormally high levels of molecules that signal this kind of growth activates ARF, which in turn allows p53 to accumulate in the cell to halt that growth.
"The importance of ARF is that it can control the two related activities, growth and division, that are key to cancer development," says Zhang. "ARF can inhibit the cell cycle by activating p53 and can also inhibit cell growth by inhibiting B23."
The study is funded by the National Institutes of Health and by M. D. Anderson Cancer Center. Zhang's co-authors include, from M. D. Anderson's Department of Molecular and Cellular Pathology: Koji Itahana, Ph.D.; Krishna Bhat, Ph.D.; Aiwen Jin, Yoko Itahana; and from the Department of Molecular Pathology: David Hawke; and Ryuji Kobayashi, Ph.D.