UCSF-led scientists have determined that under certain conditions the Ras oncogene, a key culprit in many cancers, suppresses the function of the p53 tumor-suppressor gene, offering an important insight into the development of some cancers, and an explanation for why some cancers are resistant to radiation therapy. The finding is published in the current issue of Cell.
The Ras gene is part of a molecular pathway that transmits messages for cell growth - an essential component of cell function - from the surface of the cell into the cell's nucleus. But when mutated, as it is in a third of cancers, Ras functions like a gas pedal jammed to the floor, driving a cell into growth and replication overdrive. If coupled with enough other mutations causing destabilization of the cell's growth controls, the Ras oncogene can contribute to the development of cancer.
While Ras's direct role in many cancers has been known, the new finding suggests that, by regulating the p53 tumor-suppressor gene, Ras may play an indirect role in many more, says the co-lead author of the study, Stefan Ries, PhD, a postdoctoral fellow in the laboratory of senior author Frank McCormick, PhD, director of the UCSF Comprehensive Cancer Center.
"Ras's suppression of p53 could play an important role in inactivating the tumor suppressor during the early stages of some tumor development. This may be particularly true in colon cancers," says Ries.
The p53 tumor-suppressor gene is one of several genes that serve as a protector of a cell's DNA. If DNA has been damaged, as can occur during DNA replication and cell division or as a result of an environmental injury, the gene receives a signal that it should halt the cell's cycle of growth. If the cell repairs itself, p53 releases its brake; but if the damage remains, p53 induces cell death, which prevents the cell from continued growth and, ultimately, the dividing into daughter cells containing its damaged DNA. Mutations are a form of DNA damage, and it is the accumulation of mutations in certain critical genes that nudge a cell into the uncontrolled growth that is the hallmark of cancer.
The Ras oncogene's ability to suppress p53 could explain, says co-lead author Carola Biederer, PhD, a postdoctoral fellow in McCormick's lab, why some cancers are resistant to radiation therapy. Irradiation damages a cancer cell's DNA, and the theory behind its use is that, in the face of DNA damage, p53 and other protectors of DNA health would be induced, ultimately causing death of the cancer cell.
The p53 gene is mutated in 60 percent of cancers, and its inability to function is one of the key steps undermining a cell's control of its growth. However, in 40 percent of cancers, p53 remains intact, and researchers have sought an explanation for how cells can become cancerous when this key watch guard appears to maintain function.
Now, in a cell culture study of mouse embryo fibroblasts, the researchers have shown that the Ras oncogene, itself, can deactivate p53. It does so indirectly, by inducing a protein known as Mdm2, which degrades p53. But this degradation only occurs if a gene known as p19ARF, which normally inhibits Mdm2, is mutated.
"The study indicates that in a subset of the 40 percent of cancers in which p53 remains intact, Ras is playing a role in suppressing the activity of p53," says senior author McCormick.
Notably, in colon cancers, mutations in the Ras oncogene occur quite early in the progression towards colon cancer, while p53 is degraded quite late. "Given the circumstances we've described, there could be large number of tumors in which mutant Ras plays a role in keeping p53 turned down," he says.
Phase I (toxicity) trials of drugs that inhibit Ras are under way. If they are effective, the explanation may prove to be that they prevent Ras from turning off p53. And this, in turn, could enable p53 to induce the death of the cancer cell.
Two recent findings hinted that the Ras oncogene might have a role in regulating p53. Two years ago, Israeli researchers showed that Mdm2 can be activated not just by p53 but also by growth-promoting factors on the outside of the cell that transmit their messages into the cell through the molecular relay system of which Ras is one part. The team also participated in the current study.
And last year a research group reported that Ras, in both the normal and mutated form, can turn on p53, as a way of holding its own growth-promoting activities in check. When the scientists mutated the Ras gene in cell culture, the oncogene did not cause the cell to grow, because Ras had turned on p53. (Of course, when p53 has been mutated by some factor, or disrupted by mutated p19ARF, the Ras oncogene is able to function.)
The revelations illuminate the finely tuned system of checks and balances that help maintain a cell's healthy state - and which, if disrupted, contribute to a cell's spiral into cancer.
The researchers' next step is to investigate whether the Ras oncogene suppresses p53 in mouse models and in human tumors. They also plan to investigate whether the Ras oncogene does induce resistance to radiation therapy in cells in which p53 remains in tact, by examining human tumors that have been resistant to radiation therapy.
Co-authors of the study were Douglas Woods, PhD, postdoctoral fellow in the UCSF laboratory of Martin McMahon, PhD, of the UCSF Comprehensive Cancer Center; Ohad Shifman, PhD student, at the Weizmann Institute of Science, Rehovot, Israel; Senji ShiRasawa, MD, and Takehiko Sasazuki, MD, professors of medicine at Kyushu University, Fukuoka, Japan; Martin McMahon, PhD, UCSF associate professor of molecular pharmacology, of the UCSF Comprehensive Cancer Center; and Moshe Oren, PhD, professor of biology at the Weizmann Institute of Science.
The study was funded by the David A. Wood Foundation.
Journal
Cell