National Cancer Institute

NCI Researchers Identify Molecular Switch for Protein Chaperone

A protein that plays a major role in controlling normal cell growth and promoting tumor development by acting as a chaperone to other proteins was found to require a specific chemical modification for normal function, according to a new study of heat shock protein 90 (Hsp90). This research was conducted at the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), in collaboration with other institutions* and appears in the January 12, 2007, issue of Molecular Cell**.

"This new appreciation for the way cells regulate Hsp90 activity may help us better understand more of the basic cell signal pathway alterations involved in cancer development and, hopefully, identify new targets for anticancer therapies," said NCI Director John E. Niederhuber, M.D.

After they are synthesized, most proteins must be folded into their final form in order to function normally. Hsp90 chaperones other proteins through this process by assisting in their folding and escorting them to their proper locations inside the cell. Over 100 proteins have been identified as 'clients' of Hsp90. Under stress conditions, Hsp90 production increases sharply to assist in either refolding or elimination of damaged proteins, thereby helping cells return to a normal state and increasing their ability to survive.

Hsp90 levels are elevated in many types of cancer cells. Hsp90 binding helps sustain cancer-causing mutations in certain client proteins, allowing the cells to escape growth regulation and develop into tumors. Previous studies have shown that chemical inhibitors of Hsp90 can help block cell division, encourage cell suicide, and reduce the spread of a tumor. Several different Hsp90 inhibitors are currently undergoing clinical trials to test their efficacy in the treatment of cancer.

Leonard M. Neckers, Ph.D., who led this study in the Urologic Oncology Branch in NCI's Center for Cancer Research, and his colleagues previously showed that treating cells with an inhibitor of the enzyme histone deacetylase (HDAC) had the same effect as directly inhibiting Hsp90 with drugs. HDAC removes certain chemicals, called acetyl groups, from a wide range of proteins. Adding acetyl groups to proteins at specific locations -- a process called acetylation -- is one mechanism cells use to control protein activity. HDAC inhibitors block the removal of these acetyl groups. The purpose of this current study was to understand the role of acetylation in regulating Hsp90 function.