Collapse of p53 into clumps might be linked to cancer, according to St. Jude

12/01/05

Substitution of a key amino acid in the bridge destabilizes the three-dimensional structure of this four-part molecule and permits it to form potentially disease-causing amyloid fibrils

(MEMPHIS, TENN.--Dec. 1, 2005) The disruption of a molecular bridge that holds together the molecule p53 tends to destabilize this protein, allowing it to form potentially disease-causing aggregates, or "clumps," according to a study by investigators at St. Jude Children's Research Hospital.

The mutation that causes clumps to form is associated only with the pediatric cancer adrenocortical carcinoma (cancer of the outer layer of the adrenal gland), suggesting a link between clump formation for mutant p53 in adrenal cells and the resulting cancer. Although the current finding only suggests a link between p53 clumps and adrenocortical carcinoma, mutations that disrupt various proteins have broader implications. The resulting aggregates, called amyloid fibrils, are also associated with diseases such as Alzheimer's and Parkinson's.

When the p53 gene is mutated, the defective p53 proteins that are produced cannot trigger the feedback mechanism that normally controls the protein's levels, according to Richard W. Kriwacki, Ph.D., an associate member of the Department of Structural Biology.

"The more defective p53 protein there is, the more chance there is for some of these proteins to become destabilized and form dysfunctional fibrils," said Kriwacki, senior author of a report on this work that appears in the pre-publication issue of Protein Science.

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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