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Environmental Factor, November 2012

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NIEHS researchers describe important cell signaling mechanism

By Ernie Hood

LST chief John Cidlowski, Ph.D.

Cidlowski heads the Molecular Endocrinology Group in LST. (Photo courtesy of Steve McCaw)

Robert Oakley, Ph.D.

As lead author for the paper, most of the work and analysis was a result of Oakley’s expertise. (Photo courtesy of Steve McCaw)

Scientists in the NIEHS Laboratory of Signal Transduction (LST) have discovered a mechanism by which glucocorticoids, stress hormones produced by the body to maintain homeostasis, act upon certain key cellular receptors. Since synthetic glucocorticoids are one of the most widely prescribed pharmaceuticals in the world — treating inflammatory diseases, autoimmune illnesses, organ transplant rejection, and lymphoid system cancers —understanding this signaling mechanism could lead to more precisely targeted therapeutic treatments that have increased efficacy and fewer side effects.

The research team, led by LST chief John Cidlowski, Ph.D., staff scientist Robert Oakley, Ph.D., and former research fellow Javier Revollo, Ph.D., published the paper online Oct. 8 in the Proceedings of the National Academy of Sciences (PNAS).

Cellular cross-talk

Using multiple cell types in its experiments, the Cidlowski group demonstrated that glucocorticoids act upon G protein-coupled receptors (GPCRs) by upregulating the gene expression of one signaling protein called beta-arrestin-1, while simultaneously downregulating expression of another, beta-arrestin-2. In other words, the researchers revealed that an important exchange of information was going on between receptors on the surface of a cell and those on the nucleus. This communication can either help or hinder how well GPCR-based treatments work.

“Our work shows that glucocorticoid signaling pathways ultimately may determine the effect of pharmaceuticals in humans,” Cidlowski said.

Their findings may provide the molecular basis for the clinical synergism observed with glucocorticoid-GPCR agonist combination therapies currently used to treat asthma and chronic obstructive pulmonary disease (COPD). Understanding the mechanisms that make these combinations so powerful may allow the development of other regimens involving glucocorticoids and GPCR-targeted treatments that will be more safe and effective.

Interestingly, the person who edited Cidlowski’s PNAS paper, Duke University researcher Robert Lefkowitz, M.D., just shared the 2012 Nobel Prize in Chemistry for his seminal discoveries related to GPCRs. Both Cidlowski and Lefkowitz have dedicated the majority of their careers to understanding these important receptors.

Citation: Oakley RH, Revollo J, Cidlowski JA. 2012. Glucocorticoids regulate arrestin gene expression and redirect the signaling profile of G protein-coupled receptors. Proc Natl Acad Sci U S A 109(43):17591-17596.

(Ernie Hood is a contract writer for the NIEHS Office of Communications and Public Liaison.)

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