Harvard, Duke Researchers Discover 'Off-switch' Inside Human Cells

September 23, 1996

DURHAM, N.C. -- Researchers from Harvard University and the Duke University Comprehensive Cancer Center have discovered evidence for a new kind of "off-switch" inside human cells that can deactivate one of the cell's most prevalent biochemical mechanisms for responding to chemical stimuli such as hormones.

The scientists believe their basic discovery could eventually lead to new ways to "turn off" cancer cells, whose growth is out of control. The finding also may offer a fundamentally new route to regulating cell activity to treat heart disease, neurological disorders and other medical problems, say the researchers.

In a report in the Sept. 12 Nature, the researchers reported discovering a protein called RGS10 in human cells that seems to turn off, or desensitize, G proteins.

G proteins are important "signal transducer" molecules inside every cell in the body, including heart cells and brain cells. These protein switches transmit chemical signals from the cell surface into the cell's interior, triggering a vast array of cellular processes. G proteins are switched on by receptors on the cell's surface, which themselves are activated by hormones, neurotransmitters and other external chemical signals. Neurotransmitters are substances that trigger brain cells to fire in the process of propagating nerve impulses.

"This is the first example of a class of molecules that can turn off a G protein," said Patrick Casey, associate professor of molecular cancer biology at the Duke cancer center, and an author of the Nature paper. "Essentially all other routes to desensitization, all other ways to turn off this process in the past, have been drug molecules that acted on the cell-surface receptor." However, said Casey, such drugs may be rendered impotent because of the complex transformations that receptors undergo. Thus, he said, RGS10 may constitute a more direct and effective way to control the G-protein-activated cellular machinery

"Because of the critical role that RGS proteins may play in controlling the duration of a neurotransmitter or hormone-dependent response, it is possible that these proteins may be involved in many important aspects of signal transduction within normal and diseased states of the body," said Harvard's Ernest Peralta, the paper's other senior co-author. He is professor of molecular and cellular biology at Harvard University. Other co-authors of the paper are Duke graduate and medical student Timothy Fields, and Harvard graduate student Timothy Hunt. The research was supported by the American Cancer Society and the National Science Foundation.

RGS10, belongs to a family of "regulators of G protein signaling" (RGS) proteins. Similar proteins have been found in yeast and other invertebrates. However, until the Harvard-Duke finding, no such molecule had been found in human cells.

In their experiments, the scientists began by screening a huge library of human proteins to find those that interacted with activated G proteins. Structural analysis revealed that one of the candidate proteins they discovered, which they named RGS10, was closely related to the RGS family of proteins from yeast, mouse and other organisms. Previous studies by other scientists had shown that this RGS family switches off activated G proteins in these organisms.

Further experiments by the Harvard-Duke team also detected RGS10 in living human cells, so they began studies to understand its action. These test-tube experiments revealed that RGS10 did appear to be a powerful inactivator of several different kinds of activated G proteins, removing a phosphate from the G protein to transform it to an inactive state.

The Harvard-Duke team is now performing further experiments to understand how the action of RGS10 itself is regulated within the cell.

"While this discovery is clearly important in the signaling processes, we have a long way to go in understanding exactly how it functions," Casey said. "When we understand that, we will be in a better position to design selective and specific inhibitors or enhancers of the process."
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Duke University

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