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New Player Identified in Cellular Relay Event that Suppresses Cancer

New Player Identified in Cellular Relay Event that Suppresses Cancer
New Player Identified in Cellular Relay Event that Suppresses Cancer

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DURHAM, N.C. -- Researchers at the Duke Comprehensive Cancer Center have found a new player in a molecular "relay event" that cells play out to keep themselves healthy and growing normally. When any member of the team malfunctions, cells grow unrestrained and often become cancerous.

In fact, mutations in this particular relay event -- called the TGF-beta signaling pathway -- are involved in all pancreatic cancers and 80 percent of colon cancers, said Gerard Blobe, M.D., assistant professor of medicine, pharmacology and cancer biology at Duke.

Blobe and his Duke collaborators, Robert Lefkowitz, M.D., Wei Chen, Ph.D. and Xiao-Fan Wang, Ph.D., described their findings in the Sept. 5, 2003 issue of Science.

The new cellular team member that Blobe and his collaborators uncovered is a protein called beta-arrestin, which helps regulate the strength of signals transmitted inside the cell, much as a dimmer on a light switch controls the intensity of light.

While seemingly inconsequential, the newly identified player is critical because it tempers the loud message from the "team captain," TGF-beta, which speaks to its players from outside the cell. TGF-beta is an important signaling protein that regulates how cells grow, divide, differentiate, die at the appropriate time and establish new blood vessels to nourish the cell, among other functions.

When TGF-beta's relay team of signalers fails to function properly, the resulting inbalance can lead to a variety of diseases, including cancer, heart disease and asthma, said Blobe.

"Nearly every cell in the body makes TGF-beta, and the body requires a delicate balance of TGF-beta signaling, said Blobe. "Beta-arrestin helps maintains that balance."

Too much or too little of TGF-beta can upset the cell's status quo or "homeostasis" and cause disease, so defining how TGF-beta works inside the cell is critical to developing ways of manipulating its behavior, he said.

Toward that end, Blobe's team studied how the TGF-beta protein normally engages other players inside cells. As expected, TGF-beta docked to two sites, called receptors, on a cell's surface. The process of docking or "binding" activates a series of events inside the cell that allows it to use TGF-beta for regulating normal functions.

Surprisingly, however, the second TGF-beta receptor communicated with and activated a third receptor that was previously believed to be relatively dormant. Once activated, the third receptor recruited beta-arrestin -- the previously unidentified cellular player -- onto the TGF-beta team. Beta-arrestin has long been recognized to regulate other receptors, but it has never been shown to play a role in the TGF-beta pathway until now, said Blobe.

Even more surprising, Blobe and his collaborators found that beta-arrestin pulled two of the TGF-beta receptors inside the cell -- a process called internalization. Beta-arrestin has never been known to internalize more than a single receptor at a time.

With fewer TGF-beta receptors on the cell surface, the cell becomes less responsive to signals from TGF-beta. In this way, beta-arrestin prevents TGF-beta from over-stimulating the cell.

"In effect, beta-arrestin is like an off switch that down-regulates or turns down the TGF-beta pathway," said Blobe.

Too much of TGF-beta actually turns this tumor suppressor pathway into a tumor promoting pathway, said Blobe. Although not fully understood, this change occurs when one of the team players -- usually a receptor -- is defective and doesn't accept TGF-beta's signal. The cell no longer responds to TGF-beta, so it erroneously believes there isn't enough of the protein. Hence, the cell over-produces the protein.

The excess TGF-beta overwhelms the cell in two ways. First, it promotes the overgrowth of blood vessels, a process known as angiogenesis that is a hallmark of tumors. Tumors use angiogenesis to grow new blood vessels that sustain their growth and metastasis. Second, excess TGF-beta suppresses T cells and other components of the immune system that would normally attack aberrant cells.

"We've known that TGF-beta has a dual role: it acts as a tumor suppressor under normal circumstances, and it becomes a tumor promoter when there is a defect somewhere along the pathway," said Blobe. "The key is to determine how and why it changes from tumor suppressor to tumor promoter and to develop therapeutic ways to block its negative effects."

Blobe's latest research suggests that beta-arrestin plays a role in promoting tumor growth because it links to the mitogen activated protein (MAP) kinase pathway, another tag team of molecules that relays important messages inside the cell.

The MAP Kinase pathway is downstream of a number of growth factor receptors, so it promotes growth of cells, their ability to migrate or move, and their general survival.

"It may be through the MAP Kinase pathway that TGF-beta is mediating its tumor promoting effects," said Blobe. "We are striving to identify all the partners along the TGF-beta signaling pathway and pinpoint what is causing the pathway to shift from a tumor suppressor to a tumor promoter. The ultimate goal would be to develop therapeutic ways to block its tumor-promoting effects while maintaining its tumor suppressor effects."

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