Study Describes How Cells Return To Normal After Responding To Stress

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Study Describes How Cells Return To Normal After Responding To Stress

http://www.medicalnewstoday.com/medicalnews.php?newsid=40134

CHAPEL HILL, New research from the University of North Carolina at

Chapel Hill School of Medicine describes how cells recover from heat,

cold and other stressful conditions.

The findings also could have implications for the development of new

therapies for cardiovascular diseases and neurodegenerative diseases

such as Alzheimer's.

The study, which appears in the March 2006 issue of Nature, was led

by Dr. Cam , Ernest and Hazel Craige distinguished professor

of cardiovascular medicine, chief of the Division of Cardiology and

director of the Carolina Cardiovascular Biology Center.

also is a member of the UNC Lineberger Comprehensive Cancer Center.

The research explores the role played by the protein CHIP in the

cell's response to stress. The laboratory cloned the

protein in 1999.

In the setting of stress, molecules known as heat shock proteins are

synthesized by the cell to provide protection against protein damage.

These heat shock proteins, Hsp's, are an important part of a large

protein family known as molecular chaperones. Molecular chaperones

help new or distorted proteins fold into the correct shape, which is

essential to their function.

" Molecular chaperones determine whether proteins are appropriately

folded, " said. " They help proteins to fold normally when

proteins are being made, and they help the cell to find damaged

proteins under stressful circumstances. Once those damaged proteins

are found, the cell either tries to refold them or to get rid of them

somehow. "

CHIP is a co-chaperone, meaning that it associates with the molecular

chaperone Hsp70 and regulates its activity. But CHIP also has another

function - as an ubiquitin ligase.

" Ubiquitin ligases are generally involved in tagging proteins with a

signal that allows them to be recognized by the proteasome, which is

the major garbage can for proteins in a cell, " said. " Our

model is that CHIP is the protein that is responsible for targeting

chaperone substrates for degradation. The thinking is that when a

protein is too damaged to be refolded, CHIP ubiquitinates that

protein so that it can be degraded. "

The results present a previously unknown mechanism for how the cell

determines whether or not to degrade misfolded proteins or to degrade

the heat shock proteins that have been produced so that it can then

resume its physiologic activities.

" We think that the stress response is required to protect cells from

damage during stress, but it is also important to let the cells

return to the normal condition as soon as possible, " said Dr. Shu-

Bing Qian, postdoctoral researcher in the lab and first

author of the study.

They found that during stress heat shock proteins attempt to refold

proteins. And if unsuccessful, CHIP tags those proteins for

degradation. Once all the proteins that have been tagged for

degradation have been removed by the proteasome, a barrel-shaped

complex of proteins that digests other proteins, CHIP begins to tag

the heat shock proteins themselves for degradation. Once they are all

removed, the cell can go back to business as usual.

's group has made mouse models lacking CHIP and has found

that the mice are more susceptible to many different stressful

circumstances, such as fever and heart attacks.

" That finding seems to be due to the accumulation of misfolded

proteins, " said . " Chronic dysregulation of the CHIP

molecular pathway would also be expected to be maladaptive. "

One hope is that this finding could be extended to human diseases

where a faulty stress response has already been implicated.

said there are specific diseases in which chronic protein

misfolding is critical, including neurodegenerative diseases such as

Alzheimer's, Parkinson's, and Huntington's. " So we expect that CHIP

would play an important role in cellular adaptation under those

circumstances as well. "

He said the design of drugs to enhance the activity of CHIP might be

a valid approach to treating diseases of protein misfolding or

chronic stress.

Along with and Qian, co-authors on the study include

technician Holly McDonough and postdoctoral researcher Dr.

Boellman, both of the Carolina Cardiovascular Biology Center, and

collaborator Dr. M. Cyr, associate professor of cell and

developmental biology.