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Study Creates New Road Map for Cell Activity

Findings could provide insights about disease and aid future drug development

September 4, 2014 | Dagny Stuart

Human cells are constructed in large part from proteins whose activity can be altered by the incorporation of oxygen in what are known as redox modifications.

Detecting these redox modifications as they occur in proteins is delicate work, “like trying to catch a fairy in a jar,” said Daniel Liebler, Ph.D., Ingram Professor of Cancer Research. Scientists studying cellular processes have long sought to measure redox modifications because they provide one of the normal layers of cell control. But redox disruption or oxidative stress at the cellular level can also create a pathway to diseases like cancer, diabetes or neurodegenerative diseases.

Jing Yang, Ph.D.

Jing Yang, Ph.D., and colleagues are working to identify oxygen modifications at the cellular level that can create a pathway to certain diseases.

“These modifications are fleeting and hard to capture, and when you break open cells and tissues you create these modifications accidentally and it completely obscures what was really present in the cell.”

So Liebler and Jing Yang, Ph.D., research fellow in Biochemistry, teamed with Kate Carroll, Ph.D., and Vinayak Gupta, Ph.D., from Scripps Florida, to identify these oxygen modifications.

Their new study, with Yang as first author, was published online Sept. 1 in Nature Communications.

Prior to their work, only 10 such sites of protein redox modification had been identified.

But using probes from Carroll’s lab to penetrate cells and label the protein modifications and Vanderbilt’s expertise in mass spectrometry and proteomics to analyze and identify which proteins are modified, they were able to pinpoint exactly where on the proteins these modifications happened.

The investigators have now identified 1,000 sites known to be affected by oxygen redox modifications and a majority of those sites respond to environmental changes.

“Our paper was essentially a demonstration of how to do this in intact cells without disturbing the redox state of the proteins,” said Liebler, director of the Jim Ayers Institute for Precancer Detection and Diagnosis at Vanderbilt-Ingram Cancer Center.

Daniel Liebler, Ph.D.

Daniel Liebler, Ph.D.

“We showed that we can hit the cells with a hard oxidant stress but we can also hit the cells very gently and we were able to measure redox changes in both cases. We were able to show that some proteins were highly sensitive to this and others were very resistant to it.”

Liebler said the work provides a road map for other scientists and could be useful for drug development.

“Now that we have shown how you can measure these things, people who want to study redox mechanisms in physiology and disease will know exactly what to measure and how to measure it.”

The study was supported by funding from the National Institutes of Health (U24CA159988 and GM102187).

Photo(s) By: Photos by Susan Urmy