Important insights into how cells regulate certain growth-proteins

May 8 2006

Researchers here have discovered a new mechanism used by cells - and manipulated by retroviruses - to control the making of certain essential proteins, including some involved in cancer.

The mechanism uses an enzyme called RNA helicase A (RHA), which is made by the cell.

The study by researchers with The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and the OSU College of Veterinary Medicine appears online in the journal Nature Structural and Molecular Biology.

"Our findings provide important insights into how cells regulate certain growth-proteins, many of which play an important role in cancer, and how viruses use cell mechanisms to establish an infection," says principal investigator Kathleen Boris-Lawrie, professor of veterinary biosciences and a researcher with the OSU Comprehensive Cancer Center .

The study shows, for example, that when RHA is knocked out, the spleen necrosis virus, a retrovirus Boris-Lawrie and her collaborators were studying as a vector for gene therapy, was unable to make certain proteins. Thus, RHA might be a cellular target for future antiretroviral drugs. (Current antiretroviral drugs target the virus itself, which often becomes resistant to them, rendering the drugs ineffective. Antiretroviral drugs that affect cellular targets might be less prone to resistance.)

"Retroviruses seem to take advantage of RHA to enhance production of their own proteins, and cells use it to control the amount of particular proteins they make, many of which are involved in growth control," says Boris-Lawrie.

"The cell has to keep tight control of these proteins to be sure they are not made at the wrong time."

Cells use a four-step process to make most proteins. First, the cell makes a copy of a gene. The copy is called messenger RNA, or mRNA, and it describes the structure of the needed protein. Next, the mRNA is processed to remove non-essential information. Then, the message travels from the cell nucleus to another location, the cell cytoplasm. Last, other cell machinery translates the message and assembles the protein.

The findings by Boris-Lawrie and her collaborators show that RHA can play an important role in determining whether the last step of this process - translating the message and making the protein - actually happens.

For this study, the researchers first used mass spectroscopy to identify the cell protein and learned that the protein was RHA.

Then the researchers knocked out the RHA protein and learned that the retrovirus stopped making several vital proteins.

"That suggests that the retrovirus needs RHA to make these essential proteins," says Boris-Lawrie, "and that means RHA is a potential target for antiretroviral therapy."

The researchers also learned that when RHA is knocked out, cells can no longer make a protein called junD (pronounced "june D). The regulation of junD is lost in many cancers.

The researchers examined junD because it has something important in common with the retroviral proteins. The mRNA in both cases does not pass through the processing step of the four-step protein-making process. Normally, that processing step also adds a signal to the mRNA that facilitates the final making of the protein.

Because mRNAs like those for junD and the retrovirus are not processed, and therefore lack that signal, scientists have not understood how these mRNAs are translated into protein.

Boris-Lawrie's findings help solve that long-standing puzzle. RHA provides the missing signal. It attaches to these mRNAs and allows them to be translated into protein. If RHA is missing, the proteins are not made.

During this study, Boris-Lawrie and her colleagues identified additional genes in the human genome that do not undergo the processing step and probably need RHA to be translated. Many of these genes encode proteins that help regulate cell growth and are involved in cancer.

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