January 18, 2011

Ras Protein Cancer Causation Depends On Where As Well As How

The Ras oncogene "“ frequently mutated in cancers "“ was once thought to act at the outermost region of the cell called the plasma membrane. However, researchers at Baylor College of Medicine demonstrated first in yeast and now in mammalian cells that the Ras protein also has activity in the interior of the cell called the cytoplasm, and that its effectiveness in cancer causation depends on where it is.

"In this study, we wanted to know if the cytoplasmic Ras pathway can be found in mammalian cells and if it is important for cell transformation (into cancer),"said Dr. Eric Chang, an associate professor in the Lester and Sue Smith Breast Center at Baylor College of Medicine. The Breast Center is part of the NCI-designated Dan L. Duncan Cancer Center at BCM. A report on his work appears in the journal Molecular and Cellular Biology.

"The short answer is yes,"he said. Moreover, he said, when they developed a special method for keeping the Ras protein in the plasma membrane, they found that it did not cause the cell to become cancer in an efficient manner. However, if they combined this Ras protein with another molecule called Cdc42, a protein that looks similar to Ras and concentrates in the plasma membrane, the two were very efficient at transforming the cells.

"That led us to believe that you need Ras activity from proteins from different parts of the cell to work together to cause this transformation,"said Chang.

Two theories

His group has two theories about the effect of Ras at the plasma membrane. It could exist in a transient manner there to collect growth factors and take them to the interior.

"It's the same as when the mailman goes to the post office,"he said. "He collects the mail, but if he's stuck there (as when the Ras protein was immobilized in the experiment), he cannot deliver the mail."If the Ras protein cannot deliver the growth factors to the interior of the cell, then it cannot transform the cell into cancer.

The other theory is that Ras is required to be activated in many parts of the cell at the same time to be effective in cancer change.

The finding has importance in understanding how the Ras mutation works in cancer cells, he said.

"When you ask the question of whether Ras activation is important for tumor formation, you cannot just look at whether the Ras protein has a mutation to activate. You have to know where it localizes in the cells. If it is not in the right place, that protein mutation might not be relevant,"said Chang.

Treatment strategy

One treatment strategy might prevent the Ras protein from getting into the areas where it can affect its cancerous changes, he said. This might help in establishing a model system in which to measure Ras activity from the different compartments to use as a platform for drug screening.

The method used for holding the Ras protein at the plasma membrane might also be valuable for scientists seeking to work with Ras and understand its function, said Chang.

Others who took part in this research include Chiang-Min Cheng, Huiling Li, Drs. Jian Huang and Rachel Schiff, all of BCM and St©phane Gasman of Centre National de la Recherche Scientifique & Universit© Louis Pasteur in Strasbourg, France.

Funding for this work came from the Special Program in Research Excellence from the National Cancer Institute and the National Institutes of Health.


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