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New protein identified in development of lung cancer

17.11.2004


A newly-identified protein that can flag an important tumor suppressor gene for destruction may be a key player in the development of lung cancer.



Writing in the Nov. 17 issue of the Journal of the National Cancer Institute, scientists in the Ohio State University Comprehensive Cancer Center (OSUCCC) note that the protein, called Pirh2, when overexpressed, diminishes the activity of p53 – possibly the most powerful tumor suppressor in the entire genome. When it functions normally, p53 regulates several critical cellular processes, including cell growth and death, DNA repair and angiogenesis, the formation of new blood vessels. Studies show that p53 mutation is common, occurring in at least half of all cancer.

“The p53 gene is possibly the most important ‘manager’ in a cell. When it’s not working properly, it can be disastrous,” says Miguel Villalona, associate professor of internal medicine in the Ohio State University College of Medicine and Public Health and senior author of the study. Villalona says that this is the first time Pirh2 has been implicated in the loss of p53 function in tumors.


Villalona and his colleagues identified the link between Pirh2 and the development of cancer by evaluating Pirh2 expression in human and mouse lung tumor samples and comparing it with Pirh2 expression in normal tissue from the same samples. They found that Pirh2 expression was higher in 27 of 32 (84 percent) of human lung cancers and in 14 of 15 (93 percent) of mouse tumors than it was in the normal tissue. “This is the first demonstration that Pirh2 expression is elevated in patients’ tumors and supports the notion that it may be an important molecule in the development of lung cancer, says Gregory Otterson, associate professor of internal medicine in the OSU College of Medicine and Public Health and co-author of the study.

Wenrui Duan, the lead author of the study and a research scientist in the department of internal medicine, says that when Pirh2 is overexpressed, it “acts like glue,” binding a substance called ubiquitin to p53 protein. Ubiquitin acts like a flag, telling the cell’s recycling center – the proteasome – that the proteins are ready to be destroyed. Destruction of the proteins essentially cripples p53 and opens the door to malignant transformation. Supporting that notion, the researchers discovered that p53 protein was more ubiquitinated in the mouse lung cancers than in the normal tissue, and that generally, p53 expression was lower in tumor tissue than in normal tissue.

Interestingly, additional analysis revealed that Pirh2 overexpression is not related to any mutations in p53 – only loss of function. “In effect, we’ve discovered that Prih2 is an oncogene. It promotes cancer by undermining the tumor suppressor’s ability to do its job,” says Duan. At the same time, these findings may offer scientists a possible new target for intervention.

Villalona points out that new drugs are already on the market that can inhibit the activity of the proteasome, and suggests that these drugs may be able to counter Pirh2’s oncogenic behavior by restoring p53 function. Additional studies would be needed to demonstrate that, however. “We clearly need of new ways to fight lung cancer,” says Villalona, noting that lung cancer is the leading cause of cancer death in the United States and claims more than one million lives worldwide every year.

Grants from the National Cancer Institute supported the study.

Additional investigators from Ohio State who contributed to the project include Li Gao, Lawrence Druhan, Wei-Guo Zhu and Carl Morrison.

Michelle Gailiun | EurekAlert!
Further information:
http://www.osu.edu

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